JP2001507716A - Synthesis of epothilone and its intermediates and analogues and their use - Google Patents

Abstract

  (57) [Summary] The present invention provides epothilones A and B, desepothilones A and B, and the like. The present invention also provides analogs related to epothilones A and B and intermediates useful for their preparation. The invention further provides novel compounds based on analogs of epothilone, and methods of treating cancer and cancers with an advanced multidrug resistant phenotype.

Description

DETAILED DESCRIPTION OF THE INVENTION         Synthesis of epothilone and its intermediates and analogues and their use   This application was filed on December 3, 1996, January 14, 1997, May 22, 1997, and May 5, 1997, respectively. Application Nos. 60 / 032,282, 60 / 033,767, 60/04 filed on August 29, 1997 and August 13, 1997 7,566, 60 / 047,941 and 60 / 055,533, based on provisional applications. The contents of these applications are incorporated herein by reference. The present invention Approved by live institutions with CA-28824, CA-39821, CA-GM72231, CA-62948, and A10-9355 Approved by the National Science Foundation under CHE-9504805 and made by government protection It was a thing. Field of the Invention   The present invention belongs to the field of epothilone macrolide antibiotics. In particular, the present invention relates to epothilone A, a highly specific and non-toxic antitumor therapeutic agent. And B, desoxyepothilones A and B, and the like And a method for producing the same. Further, the present invention provides a method for inhibiting multidrug-resistant cells. The present invention also provides a novel composition provided as an intermediate for epothilone production. I do.   Various references are referenced throughout this application, each of which is referenced in its entirety. And more fully describe the state of the art at the time this invention was made. It shall be assumed. Background of the Invention   Epothilones A and B are highly active antitumor agents, Isolated from terrier. The overall structure of these compounds was determined by X-ray crystal structure analysis. G., determined by Hofle. Hofle et al., Angew. Chem. Int. Ed. Engl., 1996 , 35,1 Water purification7. Total synthesis of epothilones is a crucial eye for several reasons It is a mark. Taxol is already a useful supply in ovarian and breast cancer chemotherapy source And the scope of its clinical application is expanding. G.I. Georg et al., Taxane Anticance r Agents; American Cancer Society: SanDiego, 1995. Taxol cytotoxicity Mechanisms include stabilization of microtubule assembly, at least at the in vitro level. It is. P.B. Schiff et al., Nature (London), 1979, 277, 665. I at epothilone A series of complementary forms in n vitro experiments indicate that they probably bind to protein targets. It was shown that the taxol shares the mechanical theme downstream of the site. D. M. Bollag et al., Cancer Res., 1995, 55, 2325. In addition, epothilones are cytotoxic Outperforms Taxol in terms of in vitro efficacy and further in vitro efficacy against drug resistant cells In. Multidrug resistance (MDR) is one of a series of limitations for taxol (L. M. Landino and T.L. MacDonald, The Chemistry and Pharmacology of Taxol an d its Derivatives, V. Farin, Ed. , Elsevier: New York, 1995, ch.7, p.301) Any reagent that promises to solve this problem has been the focus of attention. In addition, clinical formulations of epothilone are more direct than taxol.   Accordingly, we set out to undertake total synthesis of epothilone, and as a result A and B, the corresponding desoxyepothilones, and their analogs An effective method has been developed. The invention also relates to the use of epothilones A and B and their analogs. Novel intermediates useful for synthesis, sets derived from such epothilones and analogs Purification of products, epothilones A and B, and desoxyepothilones A and B The present invention also provides methods of using the compounds, as well as epothilone analogs, in the treatment of cancer. Forecast Unexpectedly, epothilone proved to reverse multidrug resistance in cancer cells Not only in vitro but also in vivo and in vivo As collateral-sensitive drugs that are cytotoxic to other drugs, additional drugs such as vinblastine may also be used. Individual drug at the same concentration alone when combined with cytotoxic drugs It was found to be active as a highly active synergist. In particular, the desoxyether of the present invention Pothilone has exceptional specificity as an in vivo tumor cytotoxic drug, Xyl, vinblastine, adriamycin and camptothecin (camptotheci) normal cells that are more effective than the major chemotherapeutics currently in use, including n) Low toxicity to Summary of the Invention   One object of the present invention is to provide epothilones A and B, and desoxyepothilone A and B, and a method for producing a related compound useful as an antitumor drug treatment. . Another object of the present invention is to produce epothilones A and B and their analogs. The present invention provides various compounds useful as intermediates.   A further object of the invention provides a synthetic method for the preparation of those intermediates. That is. Furthermore, an object of the present invention is to provide an Ron, including any combination of Ron and optionally a pharmaceutical carrier, It is to provide a composition useful for treating patients.   A further object of the present invention is the provision of epothilone obtained through the process of the present invention. Cancer-affected patients using a combination of the desired analog, optionally with a pharmaceutical carrier It is to provide a way to treat. BRIEF DESCRIPTION OF THE FIGURES   FIG. 1 (A) shows a retrograde synthesis analysis of epothilones A and B.   FIG. 1 (B) presents the synthesis of compound 11. (A) t-BuMe_TwoOTf, 2,6-lutidine, C H_TwoCl_Two, 98%; (b) (1) DDQ, CH_TwoCl_Two/ H_TwoO, 89%; (2) (COCl)_Two, DMSO, CH_TwoCl_Two, -78 ℃ → rt (room temperature), 90%; (c) MeOCH_TwoPPh_ThreeCl, t-BuOK, THF, 0 ° C → rt, 86%; (d) (1) p-T sOH, dioxane / H_TwoO, 50 ° C, 99%; (2) CH_ThreePPh_ThreeBr, NaHMDS, PhCH_Three, 0 ° C → rt, 76%; (e ) Phl (OCOCF_Three)_Two, MeOH / THF, rt, 0.25h, 92%.   Figure 2 shows key intermediates in the preparation of 12,13-E- and -Z-deoxyepothilone Is presented.   FIG. 3 (A) shows hydroxymethylene- and hydroxypropylene-substituted epothilos. Presents the synthesis of key iodinated intermediates used in the preparation of thiol derivatives.   FIG. 3 (B) shows hydroxymethylene- and hydroxypropylene-substituted epothilos. The present invention provides a method for preparing a derivative of a derivative, which generally comprises 12,13-E-epothilone. Wherein R is methyl, ethyl, n-propyl, and n-hexyl, Useful for preparation from E-vinyl iodide.   FIG. 3 (B) shows benzoylated hydroxymethylene-substituted desoxyepothilone. And reactions leading to hydroxymethylene-substituted epothilones (epoxides).   FIG. 4 (A) presents the synthesis of compound 19. (A) DHP, PPTS, CH_TwoCl_Two, Rt :( b) (1) Me_ThreeSiCCLi, BF_Three・ OEt_Two, THF, -78 ℃, (2) MOMCl, I-Pr_TwoNEt, Cl (CH_Two) Cl, 55 ° C; (3) PPTS, MeOH, rt; (c) (1) (COCl)_Two, DMSO, CH_TwoCl_Two, -78 ° C; then Et_ThreeN, -78 ° C → rt; (2) MeMgBr, Et_TwoO, 0 ℃ → rt, (3) TPAP, NMO, 4A mol sieves, CH_TwoCl_Two, 0 ℃ → rt; (d) 16, n-BuLi, THF, -78 ° C; then 15, THf, -78 ° C → rt; (e) (1) N-iodosuccinimide , AgNO_Three, (CH_Three)_TwoCO; (2) Cy_TwoBH, Et_TwoO, AcOH; (f) (1) PhSH, BF_Three・ OEt_Two, CH_Two Cl_Two, Rt; (2) Ac2O, pyridine, 4-DMAP, CH_TwoCl_Two, Rt.   FIG. 4 (B) presents the synthesis of compound 1. (a) 11, p-BBN, THF, rt; then PdCl_Two (dppf)_Two, Cs_TwoCO_Three, Ph3As, H_TwoO, DMF, 19, rt, 71%; (b) p-TsOH, dioxane / H_TwoO, 5 0 ° C; (c) KHMDS, THF, -78 ° C, 51%; (d) (1) HF-pyridine, pyridine, THF, rt, 97%; (2) t-BuM e_Two SiOTf, 2,6-lutidine, CH_TwoCl_Two, -25 ° C, 93%; (3) Dess-Martin periodinane, CH_TwoCl_Two, 87%; (4) HF / pyridine, THF, rt, 99%; (e) dimethyldioxirane ;, CH_TwoCl_Two, 0.5h, -50 ° C, 45% (≧ 20: 1).   FIG. 5 shows the mechanism of synthesis of the "left wing" of epothilone A.   FIG. 6 shows the mechanism of the olefin substitution pathway to epothilone A and other analogs.   FIG. 7 shows a convergence method for total synthesis of epothilone A (1) and a geminal (geminal) method. (Solvolysis method of glycal cyclopropane for introducing an (inal) methyl group) Is exemplified.   FIG. 8 presents a mirror image (enantio) selective synthesis of compound 15B.   FIG. 9 shows the structure of model systems 20B, 21B and 22B with ring-closing olefin substitution. Show the structure.   FIG. 10 illustrates the sedimentation test of natural, synthetic and desoxyepothilone A.   FIG. 11 illustrates the sedimentation test of natural, synthetic and desoxyepothilone A at 4 ° C. You.   FIG. 12 shows that (A) epothilone A (1) and (B) Taxol® (1A). 2) shows the structure.   FIG. 13 shows acyclic stericization based on a dihydropyrone matrix Study Shows how to establish a strategic relationship.   FIG. 14 shows the preparation of Intermediate 4A.   FIG. 15 shows an alternative enantioselective synthesis of compound 17A.   FIG. 16 presents a synthetic route for Intermediate 13C. (A) 1. Tributylallyltin, (S)-(- ) -BINOL 、 Ti (Oi-Pr)_Four, CH_TwoCl_Two, -20 ° C, 60%,> 95% e.e.; 2. Ac_TwoO, Et_ThreeN, DMAP, C H_TwoCl_Two, 95%; (b) 1. OsO_Four, NMO, acetone / H_TwoO, 0 ° C; NalO_Four, THF / H_TwoO; (c) 12 , THF, -20 ° C, Z isomer only, 10 to 25%; (d) Pd (dppf)_Two, Cs_TwoCO_Three, Ph_ThreeAs, H_Two O, DMF, rt. 77%.   FIG. 17 presents a synthetic route to the intermediate epothilone B (2). (A) p-TsOH , ヂ oxane / H_TwoO, 55 ° C, 71%; (b) KHMDS, THF, -78 ° C, 67%, α / β: 1.5: 1; (c) Dess-Martin periodinane , CH_TwoCl_Two(D) NaBH4, MeOH, 67% for 2 steps; (e) 1. HF / pyridine, pyridine , THF, rt, 93%; 2. TBSOTf, 2,6-lutidine, CH_TwoCl_Two, -30 ° C, 89%; 3. Death-Martin Periodinane , CH_TwoCl_Two, 67%; (f) HF / pyridine, THF, rt, 80%; (g) dimethyldioxirane, CH_TwoCl_Two,- 50 ° C, 70%.   FIG. 18 shows the protected intermediate for 8-desmethyldeoxyepothilone A Is presented.   FIG. 19 shows the synthetic route to 8-desmethyldeoxyepothilone A and S-8-desmethyl-deoxyepothilone A and trans-iodoolefin The structure of the intermediate is presented.   FIG. 20 shows (top) epothilones A and B and 8-desmethylepothilone, (Lower) Intermediate TBS ester 1 used for the preparation of desmethylepothilone A Shows the synthetic route to 0. (A) (Z) -crotyl-B [(-)-lpc]_Two, -78 ℃, Et_TwoO, then 3N N aOH, 30% H_TwoO_Two; (B) TBSOTf, 2,6-lutidine, CH_TwoCl_Two(74%, 87% ee for 2 steps); (c) O3, CH_TwoCl_Two/ MeOH, -78 ° C, then DMS, (82%); (d) t-butylisobutyryl acetate, NaH, Bu Li, 0 ° C, then 6 (60%, 10: 1); (e) Me_FourNBH (OAc)_Three, -10 ° C (50%, 10: 1 α / β); (F) TBSOTf, 2,6-lutidine, -40 ° C, (88%); (g) Dess-Martin periodinane, (90%); (h) Pd (O H)_Two, H_Two, EtOH (96%); (i) DMSO, oxalyl chloride, CH_TwoCl_Two, -78 ° C (78%); (j) methyltriphenylphosphonium bromide , NaHMDS, THF, 0 ° C (85%); (k) TBSOTf, 2,6-lutidine, CH_TwoCl_Two, Rt (87%).   FIG. 21 shows the synthesis route of 8-desmethylepothilone A. (A) Pd (dppf)_TwoCl_Two , Ph_ThreeAs, Cs_TwoCO_Three, H_TwoO, DMF, rt (62%); (b) K_TwoCO_Three, MeOH, H_TwoO (78%); (c) DCC, 4-DMAP, 4-DMAP-HCl, CHCl_Three(78%); (d) HFpyr, THF, rt (82%), (e) 3,3-dimethyldioxirane , CH_TwoCl_Two, -35 ° C (72%, 1.5: 1).   FIG. 22 shows the synthetic route to the epothilone analog 27D.   FIG. 23 shows a synthetic route to the epothilone analog 24D.   FIG. 24 shows the synthetic route to the epothilone analog 19D.   FIG. 25 shows the synthetic route to epothilone analog 20D.   FIG. 26 shows a synthetic route to epothilone analog 22D.   FIG. 27 shows a synthetic route to the epothilone analog 12-hydroxyethylepothilone. Is shown.   FIG. 28 shows the results of the sedimentation test in comparison with DMSO, epothilone A and / or B. 4 shows the activity of an epothilone analog. Structures 17-20, 22, and 24-27 are illustrated in FIG. 29-37, respectively. Compounds were added to tubulin (1 mg / ml) to a concentration of 10 μM. Was added. The amount of microtubules formed with epothilone was measured as 100%.   FIG. 29 shows the high resolution of epothilone analog # 17¹1 shows a 1 H NMR spectrum.   FIG. 30 shows the high resolution of epothilone analog # 18¹1 shows a 1 H NMR spectrum.   FIG. 31 shows the high resolution of epothilone analog # 19.¹1 shows a 1 H NMR spectrum.   FIG. 32 shows high resolution of epothilone analog # 20¹1 shows a 1 H NMR spectrum.   FIG. 33 shows the high resolution of epothilone analog # 22¹1 shows a 1 H NMR spectrum.   FIG. 34 shows the high resolution of epothilone analog # 24.¹1 shows a 1 H NMR spectrum.   FIG. 35 shows the high resolution of epothilone analog # 25.¹1 shows a 1 H NMR spectrum.   FIG. 36 shows the high resolution of epothilone analog # 26.¹1 shows a 1 H NMR spectrum.   FIG. 37 shows high resolution of epothilone analog # 27.¹1 shows a 1 H NMR spectrum.   FIG. 38 provides a schematic illustration of the effect of fractional mixing of cytotoxic drugs.   FIG. 39 shows epothilone A and epothilone analog # 1-7. Human leukemia C CRF-CEM (sensitive) and CCRF-CEM / VBL MDR (resistant) In potency was indicated by round and square brackets, respectively.   FIG. 40 shows epothilone B and epothilone analog # 8-16. Human leukemia CCRF-CEM (sensitive) and CCRF-CEM / VBL MDR (resistant) sub Efficacy on the lines was indicated by round and square brackets, respectively.   FIG. 41 shows epothilone analog # 17-25. Human leukemia CCRF-CE M (sensitive) and CCRF-CEM / VBL MDR (resistant) subline Efficacy is indicated by round and square brackets, respectively.   FIG. 42 (A) shows epothilone analog # 26-34. Human leukemia CCRF -CEM (sensitivity) and CCRF-CEM / VBL MDR (resistance) subline Efficacy was indicated by round and square brackets, respectively.   FIG. 42 (B) shows epothilone analog # 35-46. Human leukemia CCRF -CEM (sensitivity) and CCRF-CEM / VBL MDR (resistance) subline Efficacy was indicated by round and square brackets, respectively.   FIG. 42 (C) shows epothilone analog # 47-49.   FIG. 43 (A) shows the difference between MDR MCF-7 / Adr in comparison with taxol. Figure 4 shows the antitumor activity of desoxyepothilone B on seed transplantation. Control (◆) ; Desoxyepothilone B (■; 35mg / kg); taxol (▲; 6mg / kg); adriamyci (X; 1.8 mg / kg); i.p. Q2Dx5; started on day 8.   FIG. 43 (B) shows the difference between MDR MCF-7 / Adr in comparison with taxol. Figure 4 shows the antitumor activity of epothilone B against seed transplantation. Control (◆); Epochillo B (■; 25 mg / kg; non-toxic dose); Taxol (▲; 6 mg / kg; LD₅₀Half); Adria Mycin (x; 1.8 mg / kg); i.p. Q2Dx5; started on day 8.   FIG. 44 (A) shows B6D2F with B16 melanoma.₁Desoxy in mice 4 shows the toxicity of epothilone B. Weight on days 0, 2, 4, 6, 8, 10 and 12 It was measured. Control (▲); Desoxyepothilone B (○; 10 mg / kg; QDx8; 0 out of 8) Died); desoxyepothilone B (●; 20 mg / kg; QDx6; 0 of 8 died). The first day of injection Started.   FIG. 44 (B) shows B6D2F having B16 melanoma.₁Epothilone in mice B shows the toxicity of B. Body weight was measured on days 0, 2, 4, 6, 8, 10, and 12. Control (▲); epothilone B (○; 0.4 mg / kg; QDx6; toxicity of 1 out of 8); Tyrone B (●; 0.8 mg / kg; QDx5; 5 out of 8 died). Injection starts on day 1.   FIG. 45 (A) shows the desoxyeposome in nude mice with MX-1 xenografts. 3 shows comparative therapeutic effects of Tiron B and Taxol. Tumor, s.c .; drug given i.p. Q2Dx5, started on the seventh day. Control (◆); Taxol (□; 5 mg / kg; LD₅₀of Half); desoxyepothilone B (△; 25 mg / kg; non-toxic dose).   FIG. 45 (B) shows the desoxyepoepithelium in nude mice with MX-1 xenografts. 3 shows comparative therapeutic effects of Tiron B and Taxol. Tumor, s.c .; drug given i.p. Q2Dx5, started on the seventh day. Control (◆); Taxol (□; 5 mg / kg; LD₅₀of Half; administered on days 7, 9, 11, 13, 15; then 6 mg / kg, administered on days 17, 19, 23, 24, 25 ); Desoxyepothilone B (n = 3; △, ×, *; 25 mg / kg; non-toxic dose; 3 mice To mice on days 7, 9, 11, 13, 15; then 35 mg / kg on days 17, 19, 23, 24, 25 Administration).   FIG. 46 shows the desoxyepotiro of nude mice with human MX-1 xenografts. B (35 mg / kg), Taxol (5 mg / kg) and Adriamycin (2 mg / kg) The results are shown for tumor size between 8 and 18 days after implantation. Desoxyepochiro B (□), taxol (△), adriamycin (×), control (◆); i. p. treatment was performed on days 8, 10, 12, 14, and 16.   FIG. 47 shows that epothilone B ( □; 0.6 mg / kg QDx4; i.p.) and desepothilone B (△; 25 mg / kg QDx4; i.p.) Toxic. Body weight was measured daily after injection. About epothilone B, 8 out of 8 animals Animals have the toxicity to die on days 5, 6, 6, 7, 7, 7, 7, and 7, With epothilone, all six mice survived.   FIG. 48 shows high resolution of epothilone analog # 43¹1 shows a 1 H NMR spectrum.   FIG. 49 shows high resolution of epothilone analog # 45¹1 shows a 1 H NMR spectrum.   FIG. 50 shows the high resolution of epothilone analog # 46.¹1 shows a 1 H NMR spectrum.   FIG. 51 shows the high resolution of epothilone analog # 47.¹1 shows a 1 H NMR spectrum.   FIG. 52 shows the high resolution of epothilone analog # 48.¹1 shows a 1 H NMR spectrum. Detailed description of the invention   The term "linear or branched alkyl" as used herein includes methyl, ethyl , Propyl, isopropyl, t-butyl, sec-butyl, cyclopentyl, or Including, but not limited to, clohexyl. An alkyl group is a carbon atom To 14 carbon atoms, but preferably from 1 carbon atom to 9 oxygen atoms Including, acyl, aryl, alkoxy, aryloxy, carboxy, hydro Including but not limited to xy, carboxamide, and / or N-acylamino moieties It may be substituted with various non-limiting groups.   As used herein, the terms "alkoxycarbonyl", "acyl" and "alkoxy" '' Is methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, n- Butoxycarbonyl, benzyloxycarbonyl, hydroxypropyl carbonyl , Aminoethoxycarbonyl, sec-butoxycarbonyl and cyclopentylca Including, but not limited to, rubonyl. Examples of acyl groups are formyl, acetyl , Propionyl, butyryl, and penanoyl. Examples of alkoxy groups are methoxy, ethoxy, propoxy, n-butoxy, sec-butoxy Including but not limited to xy and cyclopentyloxy.   The term "aryl" as used herein refers to phenyl, pyridyl, pyryl, indian Including, but not limited to, ril, naphthyl, thiophenyl or furyl groups. Are acyl, aryl, alkoxy, aryloxy, carboxy, hydroxy Including, but not limited to, a carboxamide, or N-acylamino moiety. May be substituted with various groups. Examples of aryloxy groups are phenoxy, Including 2-methylphenoxy, 3-methylphenoxy and 2-naphthoxy, It is not limited to them. Examples of acyloxy groups include acetoxy, propanoyloxy, Including butyryloxy, pentanoyloxy and hexanoyloxy, It is not limited to.   The present invention relates to a chemotherapeutic treatment of epothilones A and B comprising a compound having the structure Provide an analog.Where R, R₀And R 'are each independently H, linear or branched alkyl And optionally hydroxy, alkoxy, carboxy, fluorine, NR₁R_Two, N- R may be substituted with hydroxyimino or N-alkoxyimino;₁Passing And R_TwoIs independently H, phenyl, benzyl, linear or branched alkyl, R ″ is CHY ＝ CHX or H, linear or branched alkyl Phenyl, 2-methyl-1,3-thiazolinyl, 2-furanyl, 3-furanyl, 4- Furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl -1,3-oxazolinyl, 3-indolyl or 6-indolyl; X is H , Linear or branched alkyl, phenyl, 2-methyl-1,3-thiazolinyl 2,2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl Lysyl, imidazolyl, 2-methyl-1,3-oxazolinyl, 3-indolyl or Is 6-indolyl; Y is H or linear or branched alkyl Z is O, N (OR_Three) Or N-NR_FourR_FiveAnd R_Three, R_FourAnd R_FiveIs an individual Independently, H or linear or branched alkyl; n is 0, 1, 2, or 3. In one embodiment, the present invention provides a compound having the structure: Here, R is H, methyl, ethyl, n-propyl, n-butyl, n-hexyl. Or CH_TwoOH, (CH_Two)_Three-OH.   Further, the present invention provides a compound having the following structure. Where R, R₀And R 'are each independently H, linear or branched alkyl And optionally hydroxy, alkoxy, carboxy, fluorine, NR₁R_Two, N- R may be substituted with hydroxyimino or N-alkoxyimino;₁Passing And R_TwoIs independently H, phenyl, benzyl, linear or branched alkyl, R ″ is CHY ＝ CHX or H, linear or branched alkyl Phenyl, 2-methyl-1,3-thiazolinyl, 2-furanyl, 3-furanyl, 4- Furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl -1,3-oxazolinyl, 3-indolyl or 6-indolyl; X is H , Linear or branched alkyl, phenyl, 2-methyl-1,3-thiazolinyl 2,2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl Lysyl, imidazolyl, 2-methyl-1,3-oxazolinyl, 3-indolyl or Is 6-indolyl; Y is H or linear or branched alkyl Z is O, N (OR_Three) Or N-NR_FourR_FiveAnd R_Three, R_FourAnd R_FiveIs an individual Independently, H or linear or branched alkyl; n is 0, 1, 2, or 3. In certain embodiments, the present invention provides a compound having the structure: You.Here, R is H, methyl, ethyl, n-propyl, n-butyl, n-hexyl. Or CH_TwoOH.   Further, the present invention provides a compound having the following structure. Where R, R₀And R 'are each independently H, linear or branched alkyl And optionally hydroxy, alkoxy, carboxy, fluorine, NR₁R_Two, N- R may be substituted with hydroxyimino or N-alkoxyimino;₁Passing And R_TwoIs independently H, phenyl, benzyl, linear or branched alkyl, R ″ is CHY ＝ CHX or H, linear or branched alkyl Phenyl, 2-methyl-1,3-thiazolinyl, 2-furanyl, 3-furanyl, -Furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl X is 1,4-oxazolinyl, 3-indolyl or 6-indolyl; H, linear or branched alkyl, phenyl, 2-methyl-1,3-thiazolini 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4- Pyridyl, imidazolyl, 2-methyl-1,3-oxazolinyl, 3-indolyl Or 6-India Y is H or linear or branched alkyl; Z is O, N (OR_Three) Or N-NR_FourR_FiveAnd R_Five, R_FourAnd R_FiveAre independent of each other. Or linear or branched alkyl; n is 0, 1, 2, or 3. Special Further, the present invention provides a compound having the following structure. Here, R is H, methyl, ethyl, n-propyl, n-butyl, n-hexyl. Or CH_TwoOH, (CH_Two)_Three-OH.   Further, the present invention provides a compound having the following structure. Where R, R₀And R 'are each independently H, linear or branched alkyl And optionally hydroxy, alkoxy, carboxy, fluorine, NR₁R_Two, N- R may be substituted with hydroxyimino or N-alkoxyimino;₁Passing And R_TwoIs independently H, phenyl, benzyl, linear or branched alkyl, R ″ is CHY ＝ CHX or H, linear or branched alkyl Phenyl, 2-methyl-1,3-thiazolinyl, 2-furanyl, 3-furanyl, 4- Fulani 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-1, X is H, straight-chain; 3-oxazolinyl, 3-indolyl or 6-indolyl; Linear or branched alkyl, phenyl, 2-methyl-1,3-thiazolinyl, 2- Furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl , Imidazolyl, 2-methyl-1,3-oxazolinyl, 3-indolyl or 6 Y is H or linear or branched alkyl; Z Are O, N (OR_Three) Or N-NR_FourR_FiveAnd R_Three, R_FourAnd R_FiveIs independent Is H or linear or branched alkyl; n is 0, 1, 2 or 3 is there.   Further, the present invention provides a compound having the following structure.   The present invention also relates to the chemotherapeutic compounds epothilones A and B, and analogs thereof. Various intermediates useful for preparing the products are provided. Accordingly, the present invention provides the following structure And provides a key intermediate to epothilone A and its analogs. Here, R is linear or branched acyl, substituted or unsubstituted aroyl or benzyl. R 'is H, methyl, ethyl, n-propyl, n-hexyl, CH_TwoOTBS or (CH_Two)_Three-OTBDPS; X is a halide . In one embodiment, the present invention relates to a compound of the above structure, wherein R is acetyl and X is iodo. Is provided.   Further, the present invention provides an intermediate having the following structure. Here, R ′ and R ″ are each independently hydrogen, linear or branched alkyl, Substituted or unsubstituted aryl or benzyl, trialkylsilyl, diarylalkyl Lucylyl, alkyldiarylsilyl, linear or branched acyl, substituted or unsubstituted X is oxygen, (OR)_Two, (SR)_Two,-(O- ( CH_Two)_n-O)-,-(O- (CH_Two)_n-S)-or-(S- (CH_Two)_n-S)-; n is 2, 3 or 4. Here, R is H or methyl.   Another analog according to the invention has the following structure: Where R is H, methyl, ethyl, n-propyl, n-butyl, n-hexyl, CH_TwoOH or (CH_Two)_Three-OH.   Further, the present invention provides an analog having the structure: Here, R is H or methyl. The scope of the invention is that C_ThreeCarbon is R or Includes those having any of the S absolute configurations, as well as mixtures thereof.   The present invention further provides analogs of epothilone A having the structure:   The present invention also provides a route for preparing intermediates for preparing epothilone. Follow Thus, the present invention provides a method for producing a Z-iodoalkene having the following structure. Where R is hydrogen, linear or branched alkyl, alkoxyalkyl, substituted Or unsubstituted aryloxyalkyl, linear or branched acyl, substituted or unsubstituted It is substituted aroyl or benzoyl. The method comprises: (a) the following structure:Having the following structure: (Wherein R ′ and R ″ are each independently a linear or branched alkyl, Methyl having xyalkyl, substituted or unsubstituted aryl or benzyl) Coupled with a ketone under appropriate conditions, the following structure: To produce a compound having (B) treating the compound produced in step (a) under suitable conditions to give the following structure: To produce a z-iodoalkene having the formula The iodoalkene is deprotected and acetylated under appropriate conditions to give the Z-iodoalkene. Producing an ester. If the coupling in step (a) is tetrahydro Using a strong acid such as n-BuLi in an inert solvent such as furan (THF), It can be carried out typically at -50 ° C or lower, preferably at -78 ° C or lower. Step (b) The principle is that N-iodine is present in a polar organic solvent such as acetone in the presence of Ag (I) such as silver nitrate. Involves a sequential reaction with dosuccinimide, typically a borohydride reagent, preferably Follows reduction conditions using Cy2BH. In the deprotection step (c), dichloromethane or the like is used. In the presence of a Lewis acid catalyst such as boron trifluoride etherate in an inert organic solvent Contact with thiol such as thiophenol, etc. In an active organic solvent, pyridine and / or 4-dimethylaminopyridine (DMA In the presence of P), an acyl halide such as acetyl chloride, or an anhydride such as acetic anhydride. Subsequent acylation at sill.   The present invention also provides a method for producing a Z-haloalkene ester having the following formula: You. In the above formula, R is hydrogen, linear or branched alkyl, alkoxyalkyl, Substituted or unsubstituted arylalkyl, linear or branched acyl, substituted or unsubstituted arylalkyl X is halogen. This method is based on (a) Construction: Oxidatively cleaving the compound having the appropriate formula to form an aldehyde intermediate, And (b) converting the aldehyde intermediate into a halomethylene transfer agent under appropriate conditions. To form a Z-haloalkene ester. One embodiment In another embodiment, X is iodine. In another embodiment, the method comprises a halometh Phlen transfer agent is Ph_ThreeP = CHI or (Ph_ThreeP⁺CH_TwoI) I^-Implemented as You. Haloalkylidene transfer agent Ph3P = CR'I, wherein R 'is hydrogen, methyl , Ethyl, n-propyl, n-hexyl, CO_TwoEt or (CH_Two)_Three-OTBDPS) using 2-substituted olefins Can also be prepared. The oxidation step (a) is carried out using a weak oxidizing agent such as male tetroxide. Can be carried out at about 0 ° C. with the aid of sodium followed by sodium periodate or Is treated with lead tetraacetate / sodium carbonate to completely cleave the terminal olefin, Provide aldehyde. In the condensation step (b), various halomethylenes such as Wittig reagents are used. Effectively performed with the agent.   Further, the present invention provides a method for producing an optically pure compound having the following structure: You. Where R is hydrogen, linear or branched alkyl, alkoxyalkyl, substituted Or unsubstituted aryloxyalkyl, linear or branched acyl, substituted or unsubstituted It is a substituted aroyl or benzoyl. This method comprises the steps of (a) allylic organometallic reagent And the following structure:With an unsaturated aldehyde having the following formula: Optionally, in parallel therewith, optically decomposes the alcohol to give the following structure: Producing an optically pure alcohol having (B) converting the optically pure alcohol produced in step (a) under suitable conditions Including alkylating or acylating to form optically pure compounds You. In one embodiment of this method, the allyl organometallic reagent is an allyl (trialkyl ) It is a stannate. In another embodiment, the condensation step is performed by using titanium tetraalkoxy. The reaction is performed using a reagent containing a SID and an optional active catalyst. In the step (a), 1,2-Additions to saturated aldehydes are performed using various allylic organometallic reagents. But typically allyl trialkyl stannates, preferably allyl tin-n-butyl Using stannate, in the presence of chiral catalyst and molecular sieve, The reaction is performed in an inert organic solvent such as a solvent. Preferably, the method comprises titanium tetraa Lucoxide, such as titanium tetra-n-propoxide, and any active catalyst This is performed using S-(-) BINOL. The alkylation or acylation step (b) comprises A typical alkylating agent such as an alkyl halide or alkyl tosylate, Alkyl triflate or alkyl mesylate, and typical acylation Agent such as acetyl chloride, acetic anhydride, benzoyl chloride, or benzoyl anhydride. In an inert organic solvent such as dichloromethane in the presence of a mild base catalyst. Will be   The present invention also provides a method for producing a ring-opened aldehyde having the structure shown below. Here, R ′ and R ″ are each independently hydrogen, linear or branched alkyl, Substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkylaryl Lucylyl, alkyldiarylsilyl, linear or branched acyl, substituted or unsubstituted It is substituted aroyl or benzoyl. The method comprises: (a) the following structure: (Where R is linear or branched alkyl, alkoxyalkyl, substituted or Unsubstituted aryloxyalkyl, trialkylsilyl, aryldialkyl Yl, diarylalkylsilyl, triarylsilyl, straight-chain or branched X is halogen, which is sil, substituted or unsubstituted aroyl or benzoyl; ) Having the following structure: (Where (OR "")_TwoIs oxygen, (OR₀)_Two, (SR₀)_Two,-(O- (CH_Two)_n-O)-,- (O- (CH_Two)_n-S)-or-(S- (CH_Two)_n-S)-; R₀Is linear or branched Branched alkyl, substituted or unsubstituted aryl or benzyl; n is 2, 3 or 4) and cross-coupled under appropriate conditions And the following structure: (Where Y is CH (OR^*)_TwoR * is a linear or branched alkyl, Alkoxyalkyl, substituted or unsubstituted aryloxyalkyl) Cross-coupling compound, then (b) formed in step (a) above. The cross-coupling compound can be deprotected under appropriate conditions to form a ring-opened compound. And The cross-coupling step (a) is suitable for this purpose. The reaction is carried out using a reagent known in the art. For example, this step involves a pre-acyl synthesis Minutes It can be carried out by hydroborate with 9-BBN. The resulting mixed mullet Then PdCl_Two(Dppf)_TwoAnd an organometallic catalyst or a known equivalent thereof, In the presence of auxiliary reagents such as cesium carbonate and triphenylarsine, Is pulled. The deprotection step (b) involves miles of p-tosic acid, etc. Acid in a mixed aqueous organic solvent system, typically dioxane-water Can be.   The present invention also provides a method for producing epothilone having the following structure.The method comprises: (a) the following structure: (Wherein R ′ and R ″ are each independently a linear or branched alkyl, substituted or Is unsubstituted aryl or benzyl, trialkylsilyl, dialkylaryl Ryl, alkyldiarylsilyl, linear or branched acyl, substituted or unsubstituted Cyclized compounds having aroyl or benzoyl) under appropriate conditions To form a deprotected cyclized compound, and oxidize the deprotected cyclized compound under appropriate conditions. And the following structure: To produce a desoxyepothilone having the formula: Epoxidized desoxyepothilone under appropriate conditions to form epothilone To do. In the deprotection step (a), a catalyst such as HF-pyridine is used, and then With t-butyldimethylsilyl triflate in the presence of a base such as, lutidine This is performed using a general process. Dess-Martin oxidation and catalysts such as HF-pyridine Further deprotection provides desoxyepothilone. The latter compound is In step (b), peracetic acid, hydrogen peroxide, perbenzoic acid, m-chloroperbenzoate Using various epoxidizing agents such as perfumed acid, in an inert organic solvent such as dichloromethane Although it can be epoxidized, dimethyldioxirane is preferred.   Further, the present invention provides a method for producing an epothilone precursor having the following structure. Where R₁Is hydrogen, or methyl; X is O, or each is A bonded halogen and OR "₀, R 'and R "are each independently hydrogen , Linear or branched alkyl, substituted or unsubstituted aryl or benzyl, tri Alkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, straight chain Or branched or unsubstituted acyl, substituted or unsubstituted aroyl or benzoyl. this Method Has (a) the following structure:Wherein R is acetyl, having the following structure: (Where Y is oxygen) with an aldehyde having the appropriate conditions To produce an aldol intermediate, which is optionally Protected under the following conditions: May produce an acyclic epothilone precursor having (B) treating the acyclic epothilone precursor under conditions that lead to intramolecular olefin substitution. Forming an epothilone precursor. In one embodiment of the method Require the presence of an organometallic catalyst under conditions leading to intramolecular olefin substitution. This In a particular embodiment of the method of the above, the catalyst comprises Ru or Mo. Coupling Step (a) is a non-nucleophilic base such as lithium diethylamide or lithium diisobutyrate. It is carried out at a sub-room temperature using propylamide, but preferably at about -78 ° C. Engineering The olefin substitution in step (b) can be carried out using a catalyst known in the art suitable for this purpose. Although it is performed, it is preferable to use Grubb's catalyst.   Further, the present invention has the following structure, and as an intermediate for the production of epothilone: Provide useful compounds. Here, R ′ and R ″ are each independently hydrogen, linear or branched alkyl, Substituted or unsubstituted aryl or benzyl, trialkylsilyl, diarylalkyl Lucylyl, alkyldiarylsilyl, linear or branched acyl, substituted or unsubstituted X is oxygen, (OR^*)_Two, (SR^*)_Two,-(O -(CH_Two)_n-O)-,-(O- (CH_Two)_n-S)-or-(S- (CH_Two)_n-S)-; R^* Is linear or branched alkyl, substituted or unsubstituted aryl or benzyl R_TwoB is a linear, branched or cyclic alkyl or a substituted or unsubstituted aryl Or benzylboranyl moiety; n is 2, 3 or 4. One embodiment In the present invention, R 'is TBS, R "is TPS, and X is (OMe)_Two Is provided. R_TwoA preferred example of B is derived from 9-BBN.   The present invention also provides a compound having the following structure. Here, R ′ and R ″ are each independently hydrogen, linear or branched alkyl, Substituted or unsubstituted aryl or benzyl, trialkylsilyl, diarylalkyl Lucylyl, alkyldiarylsilyl, linear or branched acyl, substituted or unsubstituted X is oxygen, (OR)_Two, (SR)_Two,-(O- ( CH_Two)_n-O)-,-(O- (CH_Two)_m-S)-or-(S- (CH_Two)_n-S)-; n is 2, 3 or 4. In one embodiment, the present invention provides a method, wherein R 'is TBS. , R ″ is TPS and X is (OMe)_TwoIs provided.   The invention further provides desmethylepothilone analogs having the structure: However, R is H or methyl.   The present invention provides a compound having the following structure. However, R is H or methyl.   Further, the present invention provides a trans-desmethyldeoxyepothilone analog having the following structure: Also provide.However, R is H or methyl.   Further, the present invention provides a compound having the following structure. However, R is H or methyl.   Further, the present invention provides a compound having the following structure. Wherein R is hydrogen, linear or branched alkyl, alkoxyalkyl, substituted or Is unsubstituted aryloxyalkyl, linear or branched acyl, substituted or unsubstituted R 'is hydrogen, methyl, ethyl, n- Step Ropir, n-hexyl, , CO_TwoEt or (CH_Two)_ThreeOTBDPS; And X is halogen. In one embodiment, the present invention provides a method, wherein R is acetyl and X Is an iodide.   Further, the present invention provides a method for producing a cyclic aldehyde having the following structure. Here, R is linear or branched alkyl, alkoxyalkyl, substituted or unsubstituted. Substituted aryloxyalkyl, trialkylsilyl, aryldialkylsilyl , Diarylalkylsilyl, triarylsilyl, linear or branched acyl R ′ and R ″ are each independently a substituted, unsubstituted or substituted aroyl or benzoyl; Is hydrogen, linear or branched alkyl, substituted or unsubstituted aryl or benzene Jill, trialkylsilyl, dialkylarylsilyl, alkyldiarylsi Ryl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl. You. This method (A) The following structure:Wherein X is a halogen, having the following structure: (Where R^* _TwoB is a linear or cyclic alkyl, or a substituted or unsubstituted A reel or benzylboranyl moiety; Y is (OR₀)_Two, (SR₀)_Two,-(O- ( CH_Two)_n-O)-,-(O- (CH_Two)_n-S)-or-(S- (CH_Two)_n-S)-; R₀Is , Linear or branched alkyl, substituted or unsubstituted aryl or benzyl And n is 2, 3 or 4) under appropriate conditions. And the following structure: To produce a cross-coupled compound having (B) removing the cross-coupled compound produced in the step (a) under appropriate conditions; Protecting to form a ring-opened aldehyde. In one embodiment, the present invention R is acetyl; R 'is TBS; R "is TPS;^* _TwoB is Derived from 9-BBN and Y is (OMe)_TwoProvide a method that is Cross-cut The pulling step (a) is known in the art to be suitable for this purpose This is performed using a reagent. For example, mixed borane is PdCl_Two(Dppf)_TwoEtc. Metal catalysts or their known equivalents, cesium carbonate and triphenylarsine Can be cross-coupled in the presence of The deprotection step (b) is carried out with p-tosic acid or the like. Using a mild acid catalyst, typically in a mixed aqueous organic solvent such as dioxane-water It can be carried out.   The present invention also provides a method for producing a protected epothilone having the following structure: . Here, R ′ and R ″ are each independently hydrogen, linear or branched alkyl, Substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkylaryl Ylsilyl, alkyldiarylsilyl, linear or branched acyl, substituted or Unsubstituted aroyl or benzoyl. This method (A) The following structure:Is monoprotected under suitable conditions to give the following structure: To produce a cyclic alcohol having the formula: (B) oxidizing the cyclic alcohol produced in the step (a) under appropriate conditions, Forming a protected epothilone. In one embodiment, the present invention provides , R 'and R "are TBS. ction) Step (a) involves the elimination of a base using various suitable reagents, including TBSOTf. In the presence, it is carried out in an inert organic solvent. The base is a non-nucleophilic base such as 2,6-lutidine And the solvent may be dichloromethane. The reaction is carried out at sub-room temperature, preferably Is in the range of -30C. In the oxidation step (b), Dess-Martin periodinane (Dess -Selective oxidizing agent such as -Martin periodinane) and inert such as dichloromethane Machine Performed in a solvent. The oxidation is performed at room temperature, preferably at 20-25 ° C.   Further, the present invention provides a method for producing epothilone having the following structure.This method (A) The following structure: (Wherein R ′ and R ″ are each independently hydrogen, linear or branched alkyl, Substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkyl Reelsilyl, alkyldiarylsilyl, linear or branched acyl, substituted or Is an unsubstituted aroyl or benzoyl). Deprotected under the right conditions, the following structure: To produce desoxyepothilone having (B) converting the desoxyepothilone produced in the step (a) into an eposome under appropriate conditions; Oxidizing to form epothilone. In one embodiment, the present invention provides , R 'and R "are TBS. The deprotection step (a) comprises the steps of: This is performed by a process including a reagent such as lysine. The deprotected compound is obtained in step (b) ), Epoxides of peracetic acid, hydrogen peroxide, perbenzoic acid, m-chloroperbenzoic acid, etc. Using a xylating agent, it is epoxidized in an inert organic solvent such as dichloromethane. Preferred is dimethyldioxirane.   The present invention also provides a method for producing a cyclic diol having the following structure. Here, R 'is hydrogen, linear or branched alkyl, substituted or unsubstituted aryl. Or benzyl, trialkylsilyl, dialkylarylsilyl, alkyl Diarylsilyl, linear or branched acyl, substituted or unsubstituted aroyl or Nzoyil. This method (A) The following structure: (Where R is linear or branched alkyl, alkoxyalkyl, substituted or Unsubstituted aryloxyalkyl, trialkylsilyl, aryldialkyl Yl, diarylalkylsilyl, triarylsilyl, straight-chain or branched R 'is hydrogen, linear or unsubstituted aroyl or benzoyl; Or branched alkyl, substituted or unsubstituted aryl or benzyl, trialkyl Silyl, dialkylarylsilyl, alkyldiarylsilyl, linear or A branched acyl, substituted or unsubstituted aroyl or benzoyl) The aldehyde is cyclized under appropriate conditions to provide the following structure: And the enantiomer of a protected cyclic alcohol containing α- and β-alcohol components Form a mixture of enantiomers, (B) optionally, converting the α-alcohol produced in step (a) under suitable conditions Isolation and oxidation to form a ketone, which is then reduced under appropriate conditions The enantiomer of a protected cyclic alcohol consisting essentially of β-alcohol -Forming a mixture, then (C) applying the protected cyclic alcohol produced in steps (a) and (b) Treating with a deprotecting agent under appropriate conditions to form a cyclic diol. In one embodiment, the present invention provides a method wherein R 'is TBS and R "is TPS. Offer. The cyclization step (a) uses various mild non-nucleophilic bases such as KHMDS. And in an inert solvent such as THF. The reaction is carried out at a sub-room temperature, preferably -90 ° C It is carried out at between -50C, more preferably at -78C. Non-natural α-OH diastere Isolation of the omer may be performed by any suitable method including chromatography or crystallization of the appropriate type. It is performed by a manufacturing method. Chromatography techniques suitable for this purpose are high pressure liquids. Chromatography, countercurrent chromatography, or flash chromatography including. A variety of column media are suitable, including silica or back support. No. The β-OH derivative is then converted to a selective oxidizing agent such as Dess-Martin periodinane. Oxidized using The resulting ketone is reduced using a selective reducing agent. seed The various borohydride and aluminum hydride reagents are in the evening. Preferred reducing agents are , Sodium borohydride. Processing step (c) includes various steps including HF-pyridine It can be performed using a suitable deprotecting agent.   Further, the present invention also provides a method of treating cancer in a cancer patient, the method comprising: Treating said patient with any of the analogs related to epothilone B disclosed herein. An effective amount of is administered, optionally in combination with a pharmaceutically suitable carrier. This method is applicable when the cancer is a solid tumor or leukemia. In particular, Is applicable when the cancer is breast cancer or melanoma.   The present invention also provides a pharmaceutical composition for the treatment of cancer, wherein the composition comprises Includes any of the Tyrone analogs as the active ingredient, optional but typically pharmaceutically suitable Includes carriers who have done so. The pharmaceutical composition of the present invention further comprises other therapeutically active ingredients. You may go out.   The invention further provides a method of treating cancer in a cancer patient, the method comprising: The patient is provided with a therapeutically effective amount of the above epothilone analog and a pharmaceutically suitable carrier. A. This method is applicable when the cancer is a solid tumor or leukemia. You.   The above compounds related to epothilones A and B are useful for treating cancer, especially for multidrug resistance. When present, it is useful both in vivo and in vitro. These compounds The ability of MDR as a non-substrate in the cells of According to these compounds, they are useful for treating, preventing or ameliorating cancer in cancer patients. It was shown that   Therapeutic dosages of the compounds of the present invention will vary with the nature and severity of the condition to be treated and It depends on the type of compound and its route of administration. Generally for anticancer activity Daily dose of 0.001 to 25 mg, preferably 0.001 to 1 kg of mammal body weight To 10 mg, most preferably from 0.001 to 1.0 mg, which may be single or multiple doses. It is a single dose. Usually, a dose of about 25 mg / kg is required.   To provide an effective dosage of a compound disclosed herein to a mammal, especially a human, Any suitable route of administration may be used. For example, oral, rectal, topical, parenteral, ocular, Routes such as lungs and nose are used. Dosage forms include tablets, troches, dispersions, suspensions, Includes solutions, capsules, creams, ointments, aerosols and the like.   These compositions can be used orally, rectally, topically (transdermal, aerosol, cream, Plasters, lotions and powders), parenteral (including subcutaneous, intramuscular and intravenous), eye (Ophthalmic artery), pulmonary (nasal or buccal inhalation) or nasal administration. any The most suitable route in a given case will depend on the nature and And the nature of the active ingredient. They are conveniently provided in unit dosage form And prepared by any of the methods well-known in the pharmaceutical arts.   In preparing oral dosage forms, unusual pharmaceutical vehicles can also be employed, which include: For oral liquid preparations (eg, suspensions, elixirs, and solutions), Oils, alcohols, flavors, preservatives, coloring agents, etc. , Starch, sugar, carriers such as microcrystalline cellulose, diluents, granulating agents, lubricants, Solid preparations such as powders, capsules and tablets Preferred over liquid formulations. If necessary, cover by standard aqueous or non-aqueous techniques. May be overturned. In addition to the above dosage forms, the compounds of the present invention can also be provided in controlled release means and devices. May be administered.   Pharmaceutical compositions of the present invention suitable for oral administration include capsules, cachets or tablets. May be prepared as separate units, each of which may be powder or granule, or Solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil A predetermined amount of active ingredient in the form of a emulsion is coated. These compositions are Prepared by any method known in the art. In general, the composition comprises the active ingredient And liquid carrier, finely divided solid carrier, or both, uniformly and strongly Prepared by mixing, then, if necessary, shaping the product into the desired shape I do. For example, a tablet may be compressed or molded, optionally with one or more accessory ingredients. Prepared by molding. Compressed tablets can be made into powders or granules in a suitable machine. Active ingredients in free flowing form such as binders, lubricants, and inert Prepared by mixing with a diluent or surfactant or dispersant and pressing . Molded tablets are a powdered compound moistened with an inert liquid diluent in a suitable machine. Is prepared by molding a mixture of   The invention will be better understood from the following detailed experiments. But, One skilled in the art will appreciate that the specific methods and results discussed are described in the claims set forth below. It will be readily understood that the present invention is merely illustrative. According to the present invention The methods for producing epothilones A and B, their analogs, and their intermediates are described in Will be understood to include various alternative protecting groups well known in the art. The following fruit The protecting groups used in this disclosure, including the examples, are merely illustrative.                                 Example 1 THP glycol; 13: CH_TwoCl_Two(R)-(+)-Glycidol 12 (20 g; 270 mm) in (900 ml) ol) and freshly distilled 3,4-dihydro-2H-pyran (68.1 g; 810 mmol) are converted to pyridinium p-toluenesulfone Acid salt (2.1 g; 8.36 mmol) at room temperature (rt) and the resulting solution While stirring. About 50% of the solution was then removed under vacuum and the remaining solution was washed with ether (1 L ). Next, the organic layer was divided into two portions with a saturated aqueous solution of sodium bicarbonate (500 ml). Wash and dry (Na_TwoSO_Four), Filtered and concentrated. Fresh chromatographic residue Purified by chromatography (silica, 25 → 50% ether: hexane) to give THP glycidol 13 (31.2 g; 73%) Obtained as a colorless liquid.                                 Example 2 Alcohol 13a: trimethylsilylacetylene (32.3 g; 329 mmol) is added via a syringe to THF. (290 ml), the resulting solution was cooled to −78 ° C., and n-butyllithium (1.6 M solution in hexane) was added. Liquid (154 ml; 246.4 mmol). 15 minutes later, boron trifluoride diethyl etherate (34.9 g ; 246 mmol) was added and the resulting mixture was stirred for 10 minutes. Then, THF (130ml) Epoxide 13 (26 g; 164.3 mmol) in was added via cannula and the resulting solution Was stirred at -78 ° C for 5.5 hours. For the reaction, add a saturated aqueous sodium bicarbonate solution (250 ml) And quenched the solution to room temperature. The mixture is then brought up with ether (600 ml). Dilute with saturated aqueous sodium bicarbonate (250 ml), water (250 ml), and brine (250 ml) Washed continuously. Then the organic layer was dried (Na_TwoSO_Four), Filtered and concentrated under vacuum Shrunk. The residue was purified by fresh chromatography (silica, 20% ether: hexane). And alcohol 13a (34 g; 76%).                                 Example 3 MOM ether 13b: alcohol 13a (24 g; 88.9) in anhydrous 1,2-dichloroethane (600 ml) mmol) and N, N-diisopropylethyleonamine (108 ml; 662 mmol) in chloromethyl methyl ether (17 m l; 196 mmol) and the resulting mixture was heated to 55 ° C for 28 hours. Then dark The mixture was cooled to room temperature and treated with a saturated aqueous solution of sodium bicarbonate (300 ml). Layers separated After that, the organic layer was continuously treated with a saturated aqueous solution of sodium bicarbonate (200 ml) and brine (200 ml). Was washed. Dry the organic layer (Na_TwoSO_Four), Through a silica gel pad (Eretzrinse) And filtered. The residue was subjected to fresh chromatography (silica, 20 → 30% ether: hexane ) To give MOM ether 13b (23.7 g; 85%).                                 Example 4 Alcohol 14: THP ether 13b in methanol (90 ml) was converted to pyridinium p-toluenesulfonic acid Treatment with salt (4.0 g; 15.9 mmol), the resulting mixture was stirred at room temperature for 16 hours. Next The reaction is quenched by the addition of a saturated aqueous solution of sodium bicarbonate (100 ml) and excess methanol Was removed under vacuum. The residue was diluted with ether (300 ml) and the organic layer was saturated with sodium bicarbonate. Washing was carried out successively with Japanese aqueous solution (200 ml) and brine (200 ml). Dry the organic layer ( Na_TwoSO_Four), Filtered and concentrated. The residue was subjected to fresh chromatography (silica, 40 Purification with 50% ether: hexane) gave alcohol 14 (13.1 g; 95%) as a colorless oil.                                 Example 5 Alcohol 14a: CH_TwoCl_TwoOxalyl chloride (2M CH2) in (165 ml)_TwoCl_Two24.04 ml of solution; Anhydrous DMSO (4.6 ml; 64.1 mmol) was added dropwise to a cooled solution (-78 ° C) of 48.08 mmol). 30 minutes later, CH_TwoCl_TwoAdd a solution of alcohol 14 (6.93 g; 32.05 mmol) in (65 ml + 10 ml rinse) The resulting solution was stirred at -78 ° C for 40 minutes. Then the freshly distilled triethylamine (13.4 ml; 96.15 mmol) was added, the cooling bath was removed and the mixture was warmed to 0 ° C . The reaction mixture was then diluted with ether (500 ml), twice with water (250 ml) and brine (250 ml). 250 ml). Dry the organic layer (Na_TwoSO_Four), Filter and concentrate did.   Dissolve the starting aldehyde (6.9 g) prepared in the above reaction in ether (160 ml) and bring it to 0 ° C. Warmed up. Then, methylmagnesium bromide (32.1 ml of a 3.0 M butyl ether solution; 96.15 mmol) was added. Was added and the solution was gradually warmed to room temperature. After 10 hours, the reaction mixture was cooled to 0 ° C. The reaction was quenched by the addition of a saturated aqueous solution of ammonium fluoride. Mixture with ether (200ml) And washed successively with water (150 ml) and brine (150 ml). Dried organic layer Set (Na_TwoSO_Four), Filtered and concentrated. The residue was subjected to fresh chromatography (silica , 40 → 50% ether: hexane) to give alcohol 14a (6.3 g; 85% from 14).                                 Example 6   Ketone 15: CH at room temperature_TwoCl_TwoAlcohol 14 (1.0 g; 4.35 mmol) in 4 ml (20 ml) ol. sieves and N-methylmorpholine-N-oxide (1.0 g; 8.7 mmol) with a catalytic amount of tetra-n-propyl ammonium Treatment with perruthenate and the resulting black suspension was stirred for 3 hours. Then the reaction mixture The mixture was filtered through a pad of silica gel (ether rinse) and the filtrate was concentrated in vacuo. Residual The product was purified by fresh chromatography (silica, 10% ether: hexane) and the ketone 15 (92 4 mg; 93%) as a light yellow oil.                                 Example 7 Alkene 17: a cooled solution of phosphine oxide 16 (1.53 g; 4.88 mmol) in THF (15.2 ml) (−78 ° C.) was treated with n-butyllithium (1.79 ml of a 2.45 M hexane solution). 15 minutes later, me The orange solution was treated with a solution of ketone 15 (557 mg; 2.44 mmol) in THF (4.6 ml). After 10 minutes, the cooling bath was removed and the solution was allowed to warm to room temperature. When the sediment warms, precipitates Was observed. The reaction was quenched by the addition of a saturated aqueous ammonium chloride solution (20 ml). I got it. Pour the mixture into ether (150 ml) and combine with water (50 ml) and brine (50 ml). Washed sequentially. Dry the organic layer (Na_TwoSO_Four), Filtered and concentrated. Remove the residue Purified by Resh chromatography (silica, 10% ether: hexane) and washed with alkene 17 (767 mg; 9%). 7%) as a colorless oil.                                 Example 8 Alkyl iodide formation: dissolution of alkyne 17 (3.00 g; 9.29 mmol) in acetone (100 ml) NIS (2.51 g; 11.2 mmol) and AgNO at 0 ° C._Three(0.160 g; 0.929 mmol) was added. Next The mixture was gradually warmed to room temperature. After 1.5 hours, the reaction was_TwoPut into O (250mL) Once with saturated bisulfite (40 mL) and saturated NaHCO 3_Three(40mL) once, brine (40mL) ) Once, anhydrous MgSO_FourDry on top. Gradient in hexane / ethyl acetate (10: 1-7: 1) Purification by flash chromatography on silica gel using gradient elution gave 2.22 g ( 64%) of iodide 17a was obtained as an amber oil.                                 Example 9 Reduction of alkynyl iodide: Et_TwoCyclohexene in 0 (60 mL) (1.47 mL, 17.9 mmol) To the solution was added BH3 • DMS (0.846 mL, 8.92 mmol) at 0 ° C. The reactants are then Warmed to warm. One hour later, iodide x (2.22 g; 5.95 mmol) was added to Et._TwoAdded to O. 3 O'clock After a short time, AcOH (1.0 mL) was added. After an additional 30 minutes, the solution was saturated NaHCO_ThreeTo E t_TwoExtracted with O (3 × 100 mL). Wash the combined organics then with brine (50 mL) And anhydrous HgSO_FourDry on top. On silica gel eluted with hexane / ethyl acetate (6: 1) Purification by flash chromatography yielded 1.45 g (65%) of vinyl iodide 18 as yellow Obtained as a color oil.                                Example 10 MOM removal: CH_TwoCl_Two(40 mL) in a solution of iodide 18 (1.45 g; 3.86 mmol) in thiophenol (1.98 mL; 19.3 mmol) and BF_Three・ Et_TwoO (1.90 mL; 15.43 mmol) was added at room temperature . After 22 hours, pour the reaction into EtOAc (150 mL), wash with 1 N NaOH (2 × 50 mL), Dried over anhydrous MgSO4. Silica gel using gradient elution with hexane / ethyl acetate (4: 1-2: 1-1: 1) 1.075 g (86%) of alcohol, purified by flash chromatography above 18a was obtained as a pale yellow oil.                                Example 11 Acetate formation: CH_TwoCl_TwoTo a solution of alcohol 18a (1.04 g; 3.15 mmol) in (30 mL) was added pyridine (2.52 mL, 25.4 mmol), acetic anhydride (1.19 mL, 12.61 mmol) and DMAP (0.005 g) Was added. After 1 hour, the volatiles were removed under vacuum. The resulting residue is washed with hexane / vinegar Purify by flash chromatography on silica gel, eluting with ethyl acetate (7: 1). To give 1.16 g (99%) of acetate 19 as a pale yellow oil.                                Example 12 CH_TwoCl_Two(2.34 g, 3.62 mmol) and 2,6-lutidine (1.26 mL, 10.86 m mol) solution at 0 ° C. with TBSOTf (1.0 mL, 4.34 mmol). 1.5 hours at 0 ° C After stirring for a while, the reaction mixture was quenched with MeOH (200 μL) and the mixture was further While stirring. Etch the reaction mixture_TwoDiluted with O (100 mL), 1N HCl (25 mL), water (25 mL ) And brine (25 mL). MgSO 4 solution_FourDried over, filtered and concentrated Contraction did. 5% Et in hexane_TwoBy flash chromatography on silica gel eluting with O Purification provided compound 7 (2.70 g, 98%) as a colorless foam.                                Example 13 CH_TwoCl_Two/ H_TwoA solution of compound 7 (2.93 g, 3.85 mmol) in O (20: 1, 80 mL) was treated with DDQ (5. 23g, 23.07mmol) and the resulting suspension was stirred at room temperature for 24 hours. Reaction mixing Et things_TwoDiluted with O (200 ml) and aqueous NaHCO_Three(2 × 40 mL). Et water layer_TwoO ( 3 × 40 mL) and the combined organic fractions are washed with brine (50 mL) and extracted with MgSO_FourDry in , Filtered and concentrated. The raw oil is recovered on silica gel eluting with 30% ether in hexane. Purified by flash chromatography, alcohol 7A (2.30 g, 89%) was obtained as a colorless oil. Obtained as                                Example 14 CH_TwoCl_TwoTo a solution of oxalyl chloride (414 μL, 4.74 mmol) in (40 mL) was added DMSO (448 μL, 6 .32 mmol) was added dropwise at -78 ° C, and the resulting solution was stirred at -78 ° C for 30 minutes. CH_TwoCl_Two(2 Alcohol 7a (2.12 g, 3.16 mmol) in 0 mL) and the resulting white suspension is cooled to −78 ° C. For 45 minutes. Etch the reaction mixture_ThreeQuench with N (2.2 mL, 15.8 mmol) and add solution Was warmed to 0 ° C. and stirred at this temperature for 30 minutes. The reaction mixture is_tDilute with 20 (100mL) And aqueous NH_FourWashed successively with Cl (20 mL), water (20 mL) and brine (20 mL). Raw aldehyde With 5% Et in hexane_TwoFor flash chromatography on silica gel eluting with O Further purification provided aldehyde 8 (1.90 g, 90%) as a colorless oil.                                Example 15 A solution of (methoxymethyl) triphenylphosphonium chloride (2.97 g, 8.55 mmol) in THF (25 mL) was brought to 0 ° C. KO^tTreated with Bu (8.21 mL of 1 M in THF, 8.1 mmol). The mixture is stirred at 0 ° C for 30 minutes. Stirred. Aldehyde 8 (3.1 g, 4.07 mmol) in THF (10 mL) was added and the resulting solution was added. Warmed to room temperature and stirred at this temperature for 2 hours. The reaction mixture is made up of aqueous NH_FourWith Cl (40mL) Quench and elute the resulting solution with Et_TwoExtracted with O (3 × 30 mL). Et summarized_TwoO fractionation , Washed with brine (20 ml), MgSO_FourAnd concentrated. Residue is 5% Et in hexane_TwoIn O Purification by flash chromatography on silica gel eluting gave compound 9 (2 .83 g, 86%) as a colorless foam.                                Example 16 dioxane / H_TwoTo a solution of compound 9 (2.83 g, 3.50 mmol) in O (9: 1, 28 mL) was added pTSA.H_TwoO (1.0 g, 5.30 mmol) was added and the resulting mixture was heated to 50 ° C. for 2 hours. To room temperature After cooling with Et_TwoDilute with 0 (50 mL) and add aqueous NaHCO_Three(15mL), wash with brine (20mL) Purified, MgSO_FourAldehyde, 9a (2.75 g, 99%) in colorless form. I got it as a game.                                Example 17 Methyltriphenylphosphonium bromide (1.98 g, 5.54 mmol) in THF (50 mL) was treated at 0 ° C. with lithium bis (trimethylsilyl) amide (5.04 mL of 1 M in THF, 5.04 mmol) and the resulting solution was treated. Stirred at 0 ° C. for 30 minutes. Aldehyde 9a (2.0 g, 2.52 mmol) in THF (5.0 mL) was added. The resulting solution was warmed to room temperature and stirred at this temperature for 1 hour. The reaction mixture is water Sex NH_FourQuench with Cl (15 mL) and Et_TwoExtracted with O (3 × 20 mL). Et summarized_TwoO fractionation Was washed with brine (15 mL) and MgSO_FourAnd concentrated. Residue is 5% Et in hexane_TwoO Purification by flash chromatography on silica gel, eluting with 0 (1.42 g, 76%) was obtained as a colorless foam.                                Example 18 A solution of compound 10 (1.0 g, 1.34 mmol) in MeOH / THF (2: 1, 13 mL) was added at room temperature. And treated with [bis (trifluoroacetoxy) iodobenzene] (865 mg, 2.0 lmmol). 15 minutes later, reaction Mix the aqueous NaHCO_Three(25 mL). Mixture with Et_TwoNote with O (3 x 25 mL) Et put out and put together_TwoThe O fraction was washed with brine and dried over MgSO_Four, Filtered and concentrated. Residue is 5% Et in hexane_TwoFor flash chromatography on silica gel eluting with O Further purification provided compound 11 (865 mg, 92%) as a colorless foam.                                Example 19 Suzuki coupling: solution of olefin 11 (0.680, 1.07 mmol) in THF (8.0 mL) To the mixture was added 9-BBN (0.5 M solution in THF, 2.99 mL, 1.50 mmol). In another flask, Iodide 19 (0.478 g, 1.284 mmol) was dissolved in DMF (10.0 mL). Then, Cs CO_Three(0.696 g, 2.14 mmol) was added with vigorous stirring._ThreeAs (0.034g, 0.111 mmol), PdCl_Two(dppf)_Two(0.091 g, 0.111 mmol) and H_Two0 (0.693 mL, 38.5 mmol ) Was added. After 4 hours, the borane solution was added to the iodide mixture in DMF. reaction The material turned dark brown immediately and gradually became light yellow after 2 hours. Then reactants H_TwoO (100 mL), Et_TwoExtracted with 0 (3 × 50 mL). The collected organic matter, Wash once with water (2 × 50 mL) and brine and dry with anhydrous HgSO_FourDry on top. Hexane / ethyl acetate Purified by flash chromatography on silica gel, eluting with (7: 1), 630 g (75%) of coupling compound 20 was obtained as a pale yellow oil.                                Example 20 Hydrolysis of dimethyl acetal 21: acetate 20 (0.610 g, 0.770 mmol) was added to dioxane / H20 (9: 1, 15m), p-TSA ・ H_TwoO (0.442 g, 2.32 mmol) was added. Next The mixture was then heated to 55 ° C. After 3 hours, the mixture was cooled to room temperature and Et_TwoThrow in O Entered. This solution is added to saturated NaHCO_Three(30 mL) once, brine (30 mL) once, Anhydrous MgSO_FourDry on top. Flash on silica gel eluting with hexane / ethyl acetate (7: 1). Purification by chromatography was performed to obtain 0.486 g (85%) of aldehyde 21 in pale yellow oil. Obtained as                                Example 21 Aldol: Acetate-aldehyde 21 (84 mg, 0.099 mmol) in THF at -78 ° C KHMDS (0.5 M toluene solution, 1.0 ml, 0.5 mmol) was added dropwise. The obtained solution is -78 ° C For 30 minutes. The reaction mixture was then cannulated into a short pad of silica gel. And washed with ether. The residue was purified by flash chromatography (silica, 12% Et in hexane). OAc) to give lactone 22 (37 mg 3-S and 6 mg 3-R, 51%) in white powder. Ohms.                                Example 22 Monodeprotection: Lactone 22 (32 mg, 0.0376 mmol) was dissolved in 1 ml of pyridine-buffered HF / pyridine-THF The solution was treated at room temperature for 2 hours. The reaction mixture was washed with saturated NHCO_ThreePour into water and add ether Extracted. Organic layer was washed with saturated CuSO_Four(10ml × 3) and saturated NaHCO_Three(10ml) Wash and Na_TwoSO_FourAnd concentrated in vacuo. Residues are flash chromatographed Purified by chromatography (silica, 25% EtOAc in hexane) to give diol 22a (22 mg, 99%). Obtained as a white foam.                                Example 23 Anhydrous CH_TwoCl_TwoDiol 22a (29 mg, 0.0489 mmol) and 2,6-lutidine (0.017 ml, 0.147 TBSOTf (0.015 ml, 0.0646 mmol). Next The resulting solution was then stirred at -30 C for 30 minutes. The reaction was washed with 0.5M HCl (10ml). It was quenched and extracted with ether (15 ml). The ether layer was washed with saturated NaHCO_ThreeAnd dried (Na_Two SO_Four) And concentrated in vacuo. The residue is purified by flash chromatography (silica , 8% EtOAc in hexane) to give TBS ether 22B (32 mg, 93%) as a white powder. I got it as                                Example 24 Ketone formation: CH_TwoCl_Two(2mL) in alcohol 22B (30mg, 0.0424mmol) solution at 25 ° C In, Dess-Martin periodinane (36 mg, 0.0848 mmol) was added in one portion. Then get The resulting solution was stirred at 25 ° C. for 1.5 hours. Reaction is 1: 1 saturated sodium bicarbonate: sodium thiosulfate Aqueous solution (10 ml) was added to quench and stirred for 5 minutes. The mixture is then etherified (3 × 15 ml). Dry the organic layer (Na_TwoSO_Four), Filter and concentrate under vacuum did. The residue was purified by flash chromatography (silica, 8% EtOAc in hexane). To afford ketone 22C (25 mg, 84%) as a white foam.                                Example 25 Desoxy compound: To a solution of TBS ether 22C (27 mg, 0.038 mmol) in THF (1 ml), At 0 ° C., in a plastic container, HF.pyridine (0.5 ml) was added. The resulting solution The liquid was stirred at 25 ° C. for 2 hours. Dilute the reaction mixture with chloroform (2 ml) and add saturated sodium bicarbonate (20 ml) was added very slowly. CHCl mixture_Three(20ml x 3) Was. Dry the organic layer (Na_TwoSO_Four), Filtered and concentrated in vacuo. Remove the residue Purify by Chromatography (silica, 30% EtOAc in hexane) to give the diol 23 (18m g, 99%) as a white foam.                                Example 26 Epothilone: dry CH_TwoCl_TwoOf desoxyepothilone (9 mg, 0.0189 mmol) in 1 ml 0 ° C) to the solution was added freshly prepared dimethyldioxirane (0.95ml, 0.1M in acetone) . The resulting solution was warmed to -30 ° C for 2 hours. Next, a nitrogen stream is blown into the solution. , Excess DMDO was removed. The residue was subjected to flash chromatography (silica, hexane (40% EtOAc in EtOAc) to give epothilone A (4.6 mg, 49%) as a colorless solid. 0.1 mg of the cis-epothilone diastereomer was obtained. This substance is compatible with natural epothilone A in all respects. Matched.                                Example 27 Methods for ring-closing olefin substitution: To a stirred solution of diene 24 (5 mg, 0.0068 mmol) in dry benzene (1.5 mL) was added Grubbs catalyst (2.8 mg, 0.0034 mmol) was added. After 12 hours, the catalyst (2.8 mg) was further added. After an additional 5 hours, the reaction was concentrated. Hexane / ethyl acetate (1: 1 ) Was purified by flash chromatography eluting with lactone 23 (3.5 mg, 9 mg). 4%, 2: 1 E / Z).                                Example 28 Preparation of Compound 19 Alcohol 2A: CH_TwoCl_Two(S)-(-)-1,1 in (16mL)¹-Bi-2-naphthol (259mg, 0.91m mol), Ti (O-i-Pr)_Four(261 μL; 0.90 mmol) and 4Å sieves (3.23 g) were mixed with 1 Reflux heating for hours. The mixture was cooled to room temperature and aldehyde 1 was added. After 10 minutes, The suspension was cooled to -78 C and allyltributyltin (3.6 mL; 11.60 mmol) was added. Reaction mixture The mixture was stirred at -78 ° C for 10 minutes and then placed in a -20 ° C freezer for 70 hours. Saturation NaHCO_Three(2 mL) was added and the mixture was stirred for 1 hour,_TwoSO_FourAnd then MgS O_FourAnd filtered through a pad of Celite. Flash chromatography of crude material (hexane / Ethyl acetate, 1: 1) to give alcohol 2A as a yellow oil (1.11). g, 60%).                                Example 29 Acetate 3A: CH_TwoCl_Two(12 mL) in a solution of alcohol 2A (264 mg, 1.26 mmol) DMAP (15mg; 0.098mmol), Et_ThreeN (0.45 mL, 3.22 mmol) and Ac_TwoO (0.18mL; 1.90mmo l) was added. After 2 hours, the reaction mixture was_TwoQuench with O and add EtOAc (4 × 20m L). The combined organic layers were dried over MgSO_Four, Filtered and concentrated. Hula Purified by flash chromatography (EtOAc / hexane, 1: 3) to give 3A acetate yellow Obtained as an oil (302 mg, 96%).                                Example 30 Vinyl iodide: To a solution of acetate (99 mg, 0.39 mmol) in acetone at 0 ° C._TwoO (4 drops), OsO_Four(2.5% by weight in butyl alcohol; 175 μL; 0.018 mmol) and N-methyl-morpholine-N-oxide (69 mg; 0.59 mmol) was added. The mixture was stirred at 0 ° C. for 2 hours 45 minutes, then , Na_TwoSO_FourQuenched with Transfer the solution to 10 mL of H_TwoPour into O and extract with EtOAc (5 × 10mL) did. The combined organic layers were dried over MgSO_Four, Filtered and concentrated.   THF / H_TwoTo the raw product solution in O (4 mL, 3: 1), add NaLO_Four(260mg; 1.22mmol) did. After 1.25 hours, the reaction mixture was quenched with 10 mL of H_TwoQuenched with O and concentrated. Residue E Extracted with tOAc (5 × 10 mL). MgSO_Four, Filtered and concentrated. H Rash chromatography (EtOAc / hexane, 1: 1) gave yellow oil (80 mg) Obtained, which contained an unidentified double product. This mixture is further purified Used without.   (Ph3P in 0.25 mL THF⁺CH2I) I^-(100 mg; 0.19 mmol) in solution at room temperature 0.15 mL (0.15 mmol) of HMDS (1H in THF) was added. Add the resulting solution at -78 ° C. HMPA (22 μL; 0.13 mmol) in THF (0.25 mL) and the product of the previous step (16 mg) added. The reaction mixture was then stirred for 30 minutes. After adding hexane (10 mL), The solution was extracted with EtOAc (4 × 10 mL). Dry the combined EtOAc layers (MgSO 4_Four) Then filtration Paper, and concentrated. Preparative TLC (EtOAc / hexane, 2: 3) gave vinyl iodide Obtained as a yellow oil (14 mg; 50% over three steps).                                Example 31 Iodoolefin acetate 8C: Ethyltriphenylphosphonium iodide (1.125g, 2.69mmol) NBuLi (2.5 M solution in hexanes, 1.05 mL, 2.62 mmol) was added to a suspension of Was added warm. After the disappearance of the solid material, the solution was washed at −78 ° C. with THF (20 mL). (0.613 g, 2.41 mmol). The resulting suspension is cooled at -78 ° C for 5 Vigorously stirred for 20 minutes, then warmed to -20 ° C, and sodium hexamethyldisilazane (1M THF solution, 2.4m L, 2.4 mmol). The resulting red solution was stirred for 5 minutes and the aldehyde 9C (0.33 9g, 1.34mmol) was added slowly. The mixture was stirred at -20 ° C for 40 minutes and pentane (50 mL ), Filtered through a pad of Celite and concentrated. Column chromatography of the residue Purification by chromatography (hexane / ethyl acetate, 85:15) yielded 0.202 g (10C total from vinyl acetate). (25% by weight) of vinyl iodide 8C as a yellow oil.                               Example 32 Acetal 13C: To a solution of olefin "7C" (0.082 g, 0.13 mmol) in THF (0.5 mL) was added 9 -BBN (0.5 M in THF, 0.4 mL, 0.2 mmol) was added. After stirring at room temperature for 3.5 hours And 9-BBN (0.5 M in THF, 0.26 mL, 0.13 mmol) was added. Another flask In, 8C (0.063 g, 0.16 mmol) of iodide was dissolved in DMF (0.5 mL). Then , Cs_TwoCO_Three(0.097 g, 0.30 mmol) was added with vigorous stirring, and PdCl_Two(dppf)_Two(0.01 8, 0.022 mmol), Ph_ThreeAs (0.0059 g, 0.019 mmol) and H_TwoO (0.035 mL, 1.941 mmol ) Was subsequently added. After 6 hours, the borane solution was added to the iodide mixture in DMF. Anti The reaction immediately turned dark brown and gradually became light yellow after 3 hours. Then reactants , H_TwoO (10 mL), Et_TwoExtracted with O (3 × 15 mL). The combined organic layer is_Two Wash with O (3 × 15 mL), brine (1 × 20 mL),_Four, Filtered, and concentrated Shrunk. By flash chromatography (hexane / ethyl acetate, 9: 1), 0.089 g (7 7%) of the coupled product 13C as a yellow oil.                                Example 33 Aldehyde 14C: Acetal 13C (0.069 g, 0.077 mmol) was converted into dioxane / H_TwoDissolved in O (9: 1, 1mL) Understand, pTSA ・ H_TwoO (0.045 g, 0.237 mmol) was added. The mixture is then heated to 55 ° C. Heated. After 3 hours, the mixture was cooled to room temperature and Et_TwoO, Et_TwoO (4 × 15mL ). Combine ether solution with saturated NaHCO_Three(1 × 30mL), brine (1 × 30mL) And washed with MgSO_Four, Filtered and concentrated. Flash chromatog Rafi (hexane / ethyl acetate, 3: 1) gave 0.046 g (71%) of aldehyde 14C in pale yellow color. I got it as an il.                                Example 34 Macrocycle 15C- (SR): Aldehyde 14C (0.021 g, 0.024 mmo) in THF (5 mL) l) Add KHMDS (0.5M toluene solution, 0.145 mL, 0.073 mmol) to the solution at -78 ° C. Was added. The solution was stirred at -78 ° C for 1 hour, and saturated NH_FourQuench with Cl and add ether (3 x 15 mL ). The combined organic layers were dried over MgSO_Four, Filtered and concentrated . By flash chromatography (hexane / ethyl acetate, 7: 1), 0.008 g of the desired α-alcohol 15C- (S) and 0.006 g of β-alcohol 15C- (R) were obtained as a pale yellow oil. Was.                                Example 35 Macrocycle 15C- (S): 0.5m of β-alcohol 15- (R) (0.006g, 0.0070mmol) L CH_TwoCl_TwoTo the solution at room temperature was added Dess-Martin periodinate (0.028 g, 0.066 mmol). 0. After 5 hours, more Dess-Martin periodinate (0.025 g, 0.059 mmol) was added. The resulting solution The solution was stirred at room temperature for an additional hour, then ether (2 mL) and Na_TwoS_TwoO_Three/ Saturated NaHCO_Three (3 mL, 1: 1) and treated with H_TwoPoured into O (20 mL) and extracted with ether (4 × 10 mL). Ma The stopped ether solution was added to H_TwoWash with O (1 × 30 mL), brine (1 × 30 mL),_FourDried in , Filtered and concentrated. 15C 'solution of raw ketone in MeOH / THF (2mL, 1: 1) NaBH at -78 ° C_Four(0.015 g, 0.395 mmol) was added. Allow the resulting solution at room temperature for 1 hour While stirring, saturated NH_FourQuenched with Cl and extracted with ether (3 × 15 mL). Organic layer, Mg SO_Four, Filtered and concentrated. Flash chromatography (hexane / Using ethyl acetate, 9: 1), 0.0040 g (67%) of α-alcohol 15C- (S) and 0.006 g were converted to yellow. As a color oil and 0.0006 g of β-alcohol 15C- (R) were obtained.                                Example 36 Diol 15C "": Silyl ether 15C- (S) (0.010 g, 0.012 mmol) was added to HF / pyridine. / Pyridine / THF (1 mL). The solution was stirred at room temperature for 2 hours, then Et 2_TwoO (1 mL), then add Et_TwoO / Saturated NaHCO_Three(20mL, 1: 1), Et_TwoO (4 × 10mL) Extracted. Et_TwoO solution, CuSO_Four(3 x 30 mL), saturated NaHCO_Three(1 × 30mL), brine (1 × 30 mL) and wash with MgSO_Four, Filtered and concentrated. Flash black 0.0066 g (93%) of diol 15C ″ was thinned by chromatography (hexane / ethyl acetate, 9: 1). Obtained as a yellow oil.                                Example 37 Alcohol 15C "": Diol 15C "(0.0066 g, 0.011 mmol) in 0.5 mL of CH_TwoCl_Two Add 2,6-lutidine (7 μL, 0.060 mmol) and TBSOTf (5 μL, 0.022 mmol) to the solution did. The resulting solution was stirred at -30 ° C for 0.5 hours,_TwoQuench with O (5 mL) and add Et_TwoO (4 × 10 mL). The ether solution was diluted with 0.5M HCl (1 × 10 mL), saturated NaHCO 3_Three(1 × 10 mL) and washed with MgSO_Four, Filtered and concentrated. Flash By chromatography (hexane / ethyl acetate, 93: 7), 0.0070 g (89%) of alcohol 15C "" Was obtained as a pale yellow oil.                                Example 38 Ketone 16C: alcohol 15C "" (0.006 g, 0.0083 mmol) in 0.5 mL of CH_TwoCl_TwoIn solution At room temperature, Dess-Martin periodinane (0.030 g, 0.071 mmol) was added. 1.25 hours later, Death-Martin Periodinane (0.025 g, 0.059 mmol) was further added. The resulting solution is further added at room temperature Stir for 0.75 h, add ether (1 mL) and Na_TwoS_TwoO_Three/ Saturated NaHCO_Three(2 mL, 1: 1) and treated with H_Two It was poured into O (20 mL) and extracted with ether (4 × 10 ML). The ether solution was washed with saturated NaHCO_Three( 1 × 20 mL) and MgSO 4_Four, Filtered and concentrated. Flash By chromatography (hexane / ethyl acetate, 9: 1), 0.0040 g (67%) of ketone 16C was obtained. Obtained as a pale yellow oil.                                Example 39 Desoxyepothilone B (2C): ketone 16C (0.004 g, 0.005 in THF (0.35 mL)) HF.pyridine (0.25 mL) was added dropwise to the solution (56 mmol) for 20 minutes. This solution at room temperature Stir for 1.5 hours and add CHCl_Three(2 mL), then add saturated NaHCO_Three/ CHCl_Three(20mL, 1: 1) gradually Into CHCl_Three(4 × 10 mL). CHCl summarized_ThreeLayers are dried over MgSO_FourDry with , Filtered and concentrated. Flash chromatography (hexane / ethyl acetate, 3: 1 ) Yielded 0.0022 g (80%) of desoxyepothilone B2C as a pale yellow oil.                                Example 40 Epothilone B (2): CH_TwoCl_TwoDesoxyepothilone B (0.0022 g, 0.0041 mmo) in (0.25 mL) Dimethyldioxirane (0.1 mL, 0.0095 mmol) was added dropwise to the solution of l) at -50 ° C. The resulting solution was stirred at -50 ° C for 1 hour. Dimethyloxirane and solvent are N_TwoRemoved by airflow . Purify the residue by flash chromatography (hexane / ethyl acetate, 1: 1) Yielded 0.0015 g (70%) of epothilone B (2) as a pale yellow oil,¹ 1 H NMR, mass spectrum, and [α]_DAnd matched the reference sample.                                Example 41 8-desoxyepothilone A Crotylation product: potassium tert-butoxide (1.0 M in THF, 50.4 mL, 50. 4 mmol), a stirred mixture of THF (14 mL), and cis-2-butene (9.0 mL, 101 mmol) To the solution was added n-BuLi (1.6 M in hexane, 31.5 mL, 50.4 mmol) at -78 ° C. n-B After complete addition of uLi, the mixture was stirred at -45 ° C for 10 minutes and cooled to -78 ° C. Next In addition, (+)-B-methoxydiisopinocamphenylborane (methoxydiisopinocamphenylborane) (19.21 g, 60.74 mmol) in Et_TwoO (10 mL) was added dropwise. 30 minutes later, BF_Three・ Et_TwoO (7.47mL, 60.74mmo l), then add aldehyde 4D (9.84 g, 60.74 mmol) in THF (15 mL) and stir An impossible viscous solution was produced. Shake the mixture vigorously every 10 minutes to homogenize Was. After 3 hours at -78 ° C, the reaction was quenched with 3N NaOH (36.6 g, 110 mmol) and 30% H_TwoO_Two(15mL) And the solution was refluxed for 1 hour. Et the reaction_TwoO (300 mL) and H_TwoO (100 mL), brine (30 mL) and anhydrous MgSO_FourAnd dried. Raw material valve-bulb distillation equipment To remove the ligand from the desired product. 2mmHg, low boiling by heating at 80 ℃ Point ligand was removed. Further purification of alcohol 4D is carried out using CH_TwoCl_TwoEt inside_TwoO (2% → 4 %) By flash chromatography on silica gel eluting with Smart alcohol 4D was obtained as a clear oil. Erythro selectivity is¹H NMR spectrum Was> 50: 1. The product is Mosher ester Was determined to be 87% ee.                                Example 42 TBS ether 5D: alcohol 4D (5.00 g, 21.4 mmol) in CH_TwoCl_Two(150mL) Then, 2,6-lutidine (9.97 mL, 85.6 mmol) was added. Cool the mixture to 0 ° C and add TBSOTf (9.83 mL, 42.8 mmol) was added slowly. The reaction was warmed to room temperature. 1 hour later, anti Et_TwoO (300 mL) and 1N HCl (50 mL) once, saturated NaHCO 3_Three(50mL) Wash once with brine (50 mL) and dry with anhydrous MgSO_FourAnd dried. Hexane / diethyl ether (97 : 3) purified by flash chromatography on silica gel eluting with pure olefin 5D was obtained as a clear oil.                                Example 43 Aldehyde 6D: Olefin 5D (4.00 g, 11.49 mmol) was added to 1: 1 MeOH / CH_TwoCl_Two(100mL ). Then pyridine (4.0 mL) was added and the mixture was cooled to -78 ° C. Next After the ozone was bubbled through the reaction for 10 minutes, the color changed to light blue. Then Oxygen was bubbled through the reaction for 10 minutes. Dimethyl sulfide (4.0 mL) was added and the reaction was allowed to reach room temperature. Gradually warmed up. The reaction was stirred overnight, then the volatiles were removed under vacuum . Flash chromatography on silica gel eluting with hexane / ethyl acetate (9: 1). Purification gave 3.31 g (82%) of aldehyde 6D as a clear oil.                               Example 44 Dianion addition product 7D: tert-butyryl acetate (0.635 g, 3.51 mmol) was added to THF (50 m NaH in L) (60% in mineral oil, 0.188 g, 4.69 mmol) was added at room temperature. After 10 minutes, the mixture Was cooled to 0 ° C. After another 10 minutes, n-BuLi (1.6H in hexane, 2.20 mL, 3.52 mmol) was added. It was added slowly. After 30 minutes, aldehyde 6D (1.03 g, 2.93 mmol) was added neatly. 10 minutes Later, the reaction is H_TwoQuench with O (10 mL) and Et_TwoExtracted with O (2 × 75 mL). Summarized Wash the organics once with brine (30 mL) and dry over anhydrous MgSO._FourAnd dried. The raw material reaction mixture is , Containing the diastereomer at C5 in a ratio of 15: 1. Hexane / ethyl acetate (9: 1 → Purification by flash chromatography on silica gel eluting with 7: 1) yields 0.7 23 g (47%) of the desired alcohol 7D were obtained as a clear oil.                                Example 45 Direct reduction: tetramethylammonium triacetoxyborohydride (1.54 g, 5.88 mm) in acetonitrile (4.0 mL) ol), anhydrous AcOH (4.0 mL) was added. The mixture was stirred at room temperature for 30 minutes and then Cool. Ester 7D (0.200 g, 0.39 mmol) in acetonitrile (1.0 mL solution) was added to the reaction. And stirred at −10 ° C. for 20 hours. Quench the reaction with 1N sodium-potassium tartrate (10 mL). And stirred at room temperature for 10 minutes. The solution was then saturated NaHCO_Three(25 mL) Body Na_TwoCO_ThreeWas added to neutralize. The mixture was then extracted with EtOAc (3 × 30 mL), Wash the organics once with brine (20 mL) and dry over anhydrous MgSO._FourAnd dried. Hexane / ethyl acetate (4: 1 ) Was purified by flash chromatography on silica gel, eluting with 0.100 g (5 0%) of the diol was obtained as a 10: 1 ratio of diastereomeric alcohols.                                Example 46 Diol monoprotection: Diol (1.76 g, 3.31 mmol) in CH_TwoCl_Two(100mL) Dissolved and cooled to 0 ° C. 2,6-lutidine (12.2 mL, 9.92 mmol), followed by TBSOTf (1.14 mL , 4.96 mmol) was added and the reaction was gradually warmed to room temperature. After 1 hour, the reaction was_TwoO (300 mL), once with 1N HCl (50 mL), saturated NaHCO 3_Three(50 mL) once, brine (30 mL), dry HgSO_FourAnd dried. With hexane / ethyl acetate (20: 1 → 15: 1) Purified by flash chromatography on silica gel eluting, 2.03 g (95%) Of alcohol 8D as a clear oil, which was used as a mixture of diastereomers. Was.                                Example 47 C5 ketone formation: alcohol 8D (2.03 g, 3.14 mmol) in CH_TwoCl_Two(50 mL) and Dess-Martin periodinane (2.66 g, 6.28 mmol) was added. After 2 hours, saturated NaHCO_Three/ Saturated Na_TwoS_TwoO_Three Of a 1: 1 mixture was added. After 10 minutes, the mixture is Et_TwoO (300 mL) and brine (30 mL) and dried over anhydrous MgSO_FourAnd dried. Elution with hexane / ethyl acetate (15: 1) Purified by flash chromatography on silica gel with 1.85 g (91%) of ketone (benzyl ether) ) Was obtained as a clear oil, which was used as a mixture of diastereomers. .                                Example 48 Debenzylation: Dissolve ketone (benzyl ether) (1.85 g, 2.87 mmol) in EtOH (50 mL), Pd (OH)_Two(0.5 g) was added. The mixture is then H_TwoStir under atmosphere. Three hours later, The reaction was purged with N2 and then CHCl_ThreeThrough a pad of celite washing with (100mL) Filtered. Flash chromatography on silica gel, eluting with ethyl acetate in hexane (12% → 15%) Purified by chromatography to give 1.43 g (90%) of the diastereomeric alcohol as a clear oil Was. The C3 diastereomer is a TLC-grade SiO eluting with ethyl acetate (15%) in hexane._TwoFlash Separated by Chromatography.                                Example 49 Aldehyde formation: DMSO (0.177 mL, 2.50 mmol) was added to CH_TwoCl_Two(15 mL) of oxalyl chloride (0 .11 mL, 1.25 mmol) at -78 ° C. After 10 minutes, alcohol (0.531 g, 0.9 6 mmol) CH_TwoCl_Two(14 L). After 20 minutes, TEA (0.697 mL, 5.00 mmol) was added to the reaction mixture. And then warmed to room temperature. H to reactant_TwoO (50 mL), Et_TwoO (3 × 50mL ). H organic_TwoWash once with O (30 mL) and once with brine (30 mL) and dry with anhydrous M gSO_FourAnd dried. The aldehyde was used in raw form.                                Example 50 Wittig olefination to give 9D: NaHMDS (1.0 M solution in THF, 1.54 mL, 1.5 4 mmol) in a suspension of methyltriphenylphosphonium bromide (0.690 g, 1.92 mmol) in THF (20 mL) At 0 ° C. After 1 hour, the starting aldehyde (0.96 mmol) was added to THF (5 mL). 0 After 15 minutes at ℃, H_TwoO (0.1 mL) was added and the reaction was poured into hexane (50 mL). this , Filtered through a plug of silica gel, eluting with hexane / Et20 (9: 1, 150 mL). Raw olefin Flash chromatography on silica gel, eluting 9D with ethyl acetate in hexane (5%) 0.437 g (83% for two steps) of olefin 9D as a clear oil Obtained.                                Example 51 TBS ester 10D: Olefin 9D (0.420 g, 0.76 mmol)_TwoCl_Two(15mL) And followed by 2,6-lutidine (1.33 mL, 11.4 mmol) and TBSOTf (1.32 mL, 5.73 mmol) Processed. After 7 hours, the reaction was_TwoO (100 mL), 0.2N HCL (25 mL), brine (20 mL) and then dried over anhydrous MgSO_FourAnd dried. The residue was treated with hexane / ethyl acetate (2 Purify by flash chromatography on a short pad of silica gel, eluting quickly at 0: 1). To obtain TBS ester 10D as a clear oil. Purification is rapid and silyl ester added. It was necessary to prevent water splitting.                                Example 52 Suzuki coupling: eluting acetate 13D with hexane / ethyl acetate (7: 1 → 4: 1) Purified by flash chromatography on silica gel. Hexane / ethyl acetate (2: 1 Further purification by preparative TLC eluting with (13) removes vinyl iodide 12D from acetate acid 13D. I left. The isolated yield of acid is 0.297 g (62% based on 90% purification on borane residues). there were.                                Example 53 Hydrolysis of acetate acid 13D: acetate 13D (0.220 g, 0.297 mmol) was dissolved in MeOH / H_Two Dissolve in O (2: 1, 15 mL), K_TwoCO_Two(0.300 g) was added. After 3 hours, saturate the reaction with saturated N H_FourDiluted with Cl () and CHCl_Three(5 × 20 mL). Hydroxy acid 14D, hexane / vinegar Purification by flash chromatography on silica gel, eluting with ethyl acetate (4: 1 → 2: 1) Thus, 0.146 g (70%) of purified hydroxy acid 14D was obtained.                                Example 54 Macrolactonization: DCC (0.150 g, 0.725 mmol), 4-DMAP (0.078 g, 0.64 mmol) and 4-DMAP.HCl (0.110 g, 0.696 mmol) were added to CHCl_ThreeO (80 mL) at 80 ° C. CHCl was added to this reflux solution with a syringe pump._ThreeHydroxy in Acid 14D (0.020 g, 0.029 mmol) and DMAP (0.010 g) were added over 20 hours. Siri A syringe needle was placed at the base of the condenser to maintain proper dosing. 20 hours later, reaction The mass was cooled to 50 ° C. and AcOH (0.046 mL, 0.812 mmol) was added. After 2 hours, reactants Cooled to room temperature and saturated NaHCO_Three(30 mL), washed with brine (30 mL), Na_TwoSO_FourDry I let it. Lactone 15D was purified on silica gel eluting with hexane / ethyl acetate (20: 1 → 15: 1). Purification by lash chromatography yielded 0.014 g (75%).                                Example 55 Desmethyldesoxyepothilone A (16D): lactone 15D in THF (2.0 mL) HF.pyridine (1.0 mL) was added to 0.038 g, 0.056 mmol). After 2 hours, the reaction is saturated. Sum NaHCO_Three(30mL) and CHCl_Three(5 × 20 mL). Organic matter is Na_TwoSO_Four so Let dry. Raw diol 16D is purified by silica gel eluting with hexane / ethyl acetate (3: 1 → 2: 1). And purified by flash chromatography to give 0.023 g (89%).                                Example 56 Epoxide formation: diol 16D (0.008 g, 0.017 mmol) was added to CH_TwoCl_Two(1.0mL) And cooled to -60 ° C. Then, dimethyldioxirane (0.06M, 0.570mL, 0.0034mmol) was added. It was added slowly. The reaction temperature was gradually reduced to -25 ° C. After 2 hours at -25 ° C, volatile components Was removed from the reaction at -25 ° C under vacuum. The residue obtained is CH_TwoCl_TwoMedium MeO Purified by flash chromatography on silica gel, eluting with H (1% → 2%), cis-epoxide 3 A 1.6: 1 mixture of D and the diastereomer cis-epoxide was obtained (0.0058 g, 74%). This diastereomer epoxide Was separated by preparative TLC eluting with hexane / ethyl acetate (1: 1) and after elution, the pure diastereomer I got                                Example 57 Experimental data of C-12 hydroxyepothilone analog Propyl hydroxy compound 43:Hydroxymethyl compound 46: Discussion Total Synthesis of (-)-Epothilone A   According to the present invention, a method for preparing epothilone A (1) is first known. Was. Carbons 9 to 11 are carbons 3 to 8 on the acyl side chain of McRole Acton, and And the chiral inclusion region of carbons 12 to 15 on the alkyl side chain. Three-dimensional The transfer of scientific information from one segment to another is unlikely. Therefore, adopt A different approach deals with the stereochemistry of each segment individually. In the acyl segment In the context of this strategy, the “polypropionate-like” network And knowledge of both absolute and absolute structures. In the alkyl segment There are two possibilities. One point is that C12-C13 epoxides It may be involved in building through merger with sill-related structures. In that case, carbon The relative stereochemical relationships of 15, 13 and 12 need to be protected. Epoxide Account for the possibility of elimination from the alkyl side chain via coupling. Was necessary. This approach allows macro control with acceptable stereo control. It is only feasible if the epoxide can be introduced after ring closure. Acyl fragment The synthesis of compound 4 having most of the essential stereochemical information required for is as described above. It is. This intermediate is used as the new oxidatively induced cyclopropanopyran 3 Prepared by rubolysis cleavage. Further, the above include carbons 15, 13 and 12 Alkyl Side-Chain Coupling Partner Representing Absolute and Relative Stereochemistry at Also described are structures that include a different method from the alternatives described below.   Considering the linking of the alkyl and acyl domains, several possible binding sites is there. In some places, acylation is required to form ester (or lactone) linkages (See solid arrow 2). Furthermore, the formation of C2-C3 bond requires File structure is required. To determine the exact timing of this aldol stage, Consideration needed. Acylation of C-15 hydroxyl when extending C3-C9 structure Will be considered. Unexpectedly, macrolides have been (Known points of ketoaldehyde macroaldolization) For details, see C.M. Hayward, et al., J. Am. Chem. Soc., 1993, 115, 9345). this The options are indicated by solid arrows 3 in FIG.   The first step of merging acyl and alkyl fragments (see arrow 1) is difficult There are serious synthetic obstacles. One skilled in the art will recognize carbon 9 and 10 or carbon 10 and 11 In an attempt to achieve bond formation between the epoxide and the alkyl coupling Significant reaction forces have been found to work when included by partners. these The problem with acyl and alkyl reactants is that merging across both of these bonds Due to unexpected difficulties in forming those with the appropriate complementarity. Carbon 11 And the first merger between 12 was tested. This approach is based on O-alkyl coupling. Requires the loss of the oxirane bond from the signaling partner. Test some substitutions After generalization, generalized systems 5 and 6 are tested to enter the first stage of the coupling reaction. Tested. The former column is derived from intermediate 4. Generalization system 5 De novo synthesis of the corresponding useful substitute is required (FIG. 1 (B)).   The steps from 4 to 11 are shown in Scheme 2. C-7 alcohol (compound 7), followed by cleavage of benzyl ether and oxidation of aldehyde 8. Was. Extension of the aldehyde to the terminal aryl-containing fragment 10 is performed by 9 (mixture of geometric isomers E and Z). Finally, Solvolysis Tiger Oxidative cleavage of dithiane bonds under solcolytic trapping conditions To produce a specific coupling component 11 (G. Stork; K. Zhao, Tetrahedron L. ett. 1989, 30, 287).   Commercially available (R) -glycidol 12 via its THP derivative 13 Synthesis of alkyl fragments starting from those converted to 14. Tetrahydro After cleavage of the pyranbronck group, the resulting alcohol is methylketo, as shown. 1 Converted smoothly to 5. Emons type using phosphine oxide 16 Was homologated. D. Meng et al., J. Org. Chem., 1996, 61, 7998. By coupling, the trans-isomer is better than the ca. 8: 1 mixture of olefin stereoisomers 17 was obtained. The produced alkyne 17 is converted to Z-iodine via compound 18. Alkene 19 was used (see FIG. 4A). E.J.Corey et al., J.Am.Chem.Soc., 19 85,107,713.   An important first-stage coupling of the two fragments is a B-alkyl Suzuki charcoal. Achieved by elemental-carbon bond construction. N. Miyaura et al., J. Am. Chem. Soc., 1989 , 111, 314; N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457. Thus, before Hydroboration of acyl fragment 11 is achieved by its reaction with 9-BBN. Achieved. Under the conditions given, the mixture cross-coupled to iodoolefin 19 The combined borane produced 20 in 71% yield. (FIG. 4 (B)) Acetal cleavage At this time, aldehyde 21 was obtained.   As a result, the methyl group of the C-1 bonded acetoxy functional group becomes macro Explore strategies that act as nucleophiles in aldolization. Wear. See C.M. Hayward et al., Supra. Deprotonation is carried out at -78 ° C in THF. Achieved using lium hexamethyldisilazide. Unexpectedly, these Conditions show highly stereoselective macroaldolisation, which is shown as a result As a result, C-3 (S) -alcohol 22 is produced. Precursor potassium aldrate to c a. It is desirable that 22 be higher by weight when quenched at 0 ° C. Aldo Protonation of the latet at lower temperature detected more C-3 (R) compound . In fact, under some treatments, the C-3 (R) epimer is dominant. But Therefore, in the quenching of the analytical scale, C-3 (R): C-3 (S ) Ratio. In preparation scale experiments, 22 vs. C-3 The ratio of the pimers is 6: 1.   When the supply of compound 22 was completed, desoxyepothilone (23) was obtained. The quasi-target has become possible. The purpose of this is to make the triphenylsilyl (T PS) group, followed by selective silylation of C-3 alcohol, C-5 alcohol Achieved by oxidation of coal and finally fluoride-induced cleavage of two silyl ethers Is done.   The known crystal structure of epothilone (Hofle et al., Supra) allows model experiments. This is possible because the oxirane is located around the convex part of the macrolide. Suggests that Under the conditions shown, 23 dimethyldioxiranes were used. Oxidation was performed. The main product of this reaction is (-) epothilone A (1), Identification of nmr, infrared, mass spectrum, optical rotation and chromatographic This was done by torographic comparison. Hofle et al., Supra. Epothilone A (1) In addition to a small amount of the diepoxide mixture and a small amount of the diastereomer cisC12- C13 monoepoxide (≧ 20: 1) was detected.   The synthetic methods disclosed herein provide a harvestable and practical amount of epothilone A. More importantly, the process involves homologues, analogs and analogs not possible from the natural product itself. Provides a route to derivatives. Studies on the synthesis of epothilone A: Hydration for the management of acrylic stereochemistry Using the Ropiran template   Synthesis of enantiomerically pure equivalents of alkoxy segments (carbons 9-15) It was performed as a model experiment. The key principle is that the stereochemical tendency is (S) -lactoate Transcription from a aldehyde derivative to a new dihydropyran is involved. The latter is Addition and decomposition of the thiazole moiety enantiomerically converts the desired acrylic fragment Give in pure form.   The synthesis of epothilones is difficult due to various novel structural properties. Thiazole Part and cis epoxide and geminal dimethyl gr ouping) is a key problem to be solved. An interesting feature is the molecular A sequence of three consecutive methylene groups that serves to isolate two functional domains. You. The need to surround such achiral "spacer elements" Actually complicates the perspective for chirality transcription and contributes two stereochemically It seems that you need a strategy to merge the structures. The present invention Provides the synthesis of compound 4A (FIG. 14), but in principle such a structure H It is assumed that it can be converted to Ron itself and related shield candidates.   By identifying compound 4A as a synthetic intermediate, the stereochemistry of the acrylic intermediate can be controlled. The power of the hydropyran matrix in treating problems with control has been demonstrated. The The synthesis of hydropyrones involves the preparation of suitably active dienes and aldehyde heterodienophiles. Already disclosed by the amount required for overall cyclocondensation of ing. Danishefsky, S.J. Aldrichimica Acta, 1986,19,59. Such a matrix In the configuration of the matrix (FIG. 13) (reference: 5A + 6A → 7A), the stereoselectivity is large. It is recognized that there is a significant error range. In addition, the hydrofrump platform Are useful in various stereospecific reactions (see Schemes 7A → 8A). Even better In addition, the products of these reactions follow the ring opening scheme and the resulting steric A non-cyclic fragment having a chemical relationship is generated (see schemes 7A → 8A). Danish efsky, S.J.Chemtracts, 1989, 2,273.   The present invention provides an application of such two routes for the synthesis of compound 4A. You. Route 1 does not include control of the absolute configuration problem itself, Start at 0A. Shafiee, A., et al., J. Heterocyclic Chem., 1979, 16,1563; Sh afiee, A .; Shahocini, S.J. Heterocyclic Chem., 1989, 26, 1627. Conversion provides Enal 12A. Condensed cyclization of 12A with known dienes (Danishefsk y, S.J.; Hitahara, T.J.Am.Chem.Soc., 1974,96,7807), BF_ThreeUsing catalyst, Jihi A racemic form of dropyrone 13A results. Formation by reduction of 13A under Luche conditions Compound 14A is provided. Luche, J.-L. J. Am. Chem. Soc., 1978, 100, 2226. In order to analyze glycal derivatives by enzyme-mediated kinetic analysis, Pase methodology was available. Berkowitz, D.B. and Danishefsky, S.J.Tetrah edron Lett., 1991, 32, 5497; Berkowitz, D.B .; Danishefsky, S.J .; Schulte, G.K.J.A. m. Chem. Soc., 1992, 114, 4518. Thus, in the presence of isopropyl acetate, The lipase 30 was allowed to act on rubinol 14A, and the following Wong (Hsu, S.-H., et al., T etrahedron Lett., 1990, 31, 6403), with a mirror with acetate 15A. An enantiomerically related free glycal 16A was produced. Compound 15A And proceeded to the PMB protection system 17A. In this section, the applicant has already shown Other reaction types that have been used could be used. Therefore, dimethyldioxira And Engl., 19A (Danishefsky, S.J .; Bilodeau, M.T.Angew.Chem.Int.Ed.Engl., 19) 96,35,1381) produces an intermediate (probably the corresponding glycal epoxide) Which can be used to convert formic aldehyde 18A by treatment with sodium metal periodate. Generated. Allylation of 18A produces carbinol 19A and the formate Survive (for confirmation of allylation, see Yamamoto, Y .; Asao, N. Chemy Rev. 1993, 93, 2207). However, 19A has its anti stereoisomer (here [4: 1]. Following mesylation of secondary alcohols Deprotection (see 19A → 20A) and cyclization as indicated to give compound 4A Obtained.   In this synthesis, only about half of the dihydropyrone is guaranteed by kinetic analysis Was done. On the other hand, theoretically, the synthetic strategy considered involves obtaining epothilone itself. Use of each enantiomer of 15A for integration of all enantiomers Another route was required to be able to. The logic of this route is “dummy” The chirality of the chiral center is determined by the variable diastere Transmission to the merged pyran in accordance with the principle of Leo selection (Danishefsky, supr a). Condensed cyclization of the proposed diene with the lactaldehyde derivative 21A (Heathcock, CH , et al., J. Org. Chem., 1980, 45, 3846) under apparent chelation control. , 22A. As shown, the side chain ether is (22A → 23A → 24A → 25A) Convertible to methyl ketone. Finally, phosphine oxide 26A Of 25 A with Emmons condensate (eg, Lythgoe, B., et al.,. Tetrahedron Lett. ., 1975,3863; Toh, H.T.; Okamura, W.H.J.Org.Chem., 1983,48,1414; Baggioli ni, E.G., et al., J. Org. Chem., 1986, 51, 3098) as shown in FIG. Transformed into phosphine oxide 26A (following the procedure described in Toh, supra) and converted to 27A (Known 2-methyl-4-chloromethylthiazole (Marzoni, G.J.H.) eterocyclic Chem., 1986, 23, 577)). 17A of linear protective group adjustment I went to. This route gives a mirror image selection to the subsequently guided stereocenter and then Demonstrates the concept of stereochemical imprinting with carbon centers that gradually merge in planar morphology are doing. Based on dihydropyrone to guarantee the stereochemical element of epothilone The use of logic, as well as proof of possible strategies for macrocyclization, is described in the following sections. Synthesis of Epothilone A: Stereocontrolled Configuration of the Acyl Region and a Model of Macrocyclization   Ring Forming Olefin Substitution for Construction of 16-Membered Ring Analogues Related to Epothilone A Using. The stereospecific synthesis of the C3-C9 sector of the acyl fragment Achieved using oxidative ring opening of cyclopropanated glycals.   Disclosed in the preceding paragraph is the "alkoxy" of epothilone (1) containing 10 to 21 carbon atoms. This is the synthesis of the “S” segment (see Figure 7, compound 2B). Combination of other fragments encoding stereochemical information of silsection elements 3 to 9 It is good. Aldehyde center of formal target 3B (C_Three) Is intermolecular or intramolecular The nucleophilic structure derived from compound 2B by any of the methods (as shown in FIG. 7) , Requires the placement of a two-carbon insert). . Under these circumstances, C_ThreeOf the Secondary Alcohol Center Required in Chromatography Studies must be treated individually. One interesting feature of system 3B is that carbon 4 ( (Epothilone numbering). Proper composition decomposition (Diassembly), and again, a ring matrix corresponding to a viable equivalent of system 3B. The dihydropyran strategy is used in the construction of the tricks. gem-dimethyl A dihydropyran paradigm involving the synthesis of cyclic or acyclic fragments containing I hoped to be elaborated. The specific reaction type for this purpose is 4B → 5B Generalization under the title of Transformation (see FIG. 7). Reference to the nature of electrophile E Avoid. Therefore, the generalized target 3B where reduction is intended from structural type 5B No question was raised as to whether or not to proceed.   The starting step is a diene-aldehyde condensation cyclization reaction (FIG. 8; Danishefsky, S.J., Ald. richmica Acta, 1986, 19, 59). Examples are readily available enantiomerically homologous aldehydes 6B and dienes 7 already obtained. Chelation control in merging with B is used. Danishefsky, S.J. et al; J. Am. Chem. Soc., 1979, 101, 7001. In fact, under the action of titanium tetrachloride The single isomer shown as compound 8B was formed. Normal stereochemically sound person Method (Danishefsky, S.J .; Chemtracts Org. Chem. 1989, 2,273.) Is It is reduced to the corresponding glycal 9B. At this point, glycal 9B is A Simmons-Smith reaction was available directly to convert to bread 10B. Weinstein, S .; Sonnenberg, J.J. Am. Chem. Soc., 1961, 83, 3235; Dauben, W.G .; Berezi n, G.H.J.AmChem.Soc., 1963,85,468; Furukawa, J., et al., Tetrahedron, 1968,24,5 3; For selective examples, see Soekman, R.K.Jr .: Charette, A.B .; Asberom, T .; Johnston, B.H.J.Am.Chem.Soc., 1991,113,5337; Timmers, C.M.; Leeuwenurgh, M.A.; Verheijen , J.C .; Van der Marel, G.A .; Van Boom, J.H.Tetrajedron: Asymmetry, 1996, 7, 49. Teru. This compound is in fact, in a sense, a cyclopropanobarge of C-glycoside. It is an interesting structure in that it is equivalent to an alternative. At the same time, cyclopropane is Part of the ropircal vinyl alcohol system, with the potential for reorganization I have. Wenkert, E., et al., J. Amer. Chem. Soc., 1970, 92, 7428. In order to cleave the C-glycoside bond of cyclopropane, As a result, a solvent-derived glycoside having a desired aldehyde oxidation state is formed on C-3. (See FIG. 7, assumed conversion 4B → 5B). In earlier studies, the planned response ( That is, E⁺= H⁺The non-oxidized version of) was not practically applicable. Instead Thus, a product that can clearly contribute to the ring expansion system 11 was confirmed. For example When acidic methanol is allowed to act on 10B, oxocarbenium ion is probably Mixture of 7-membered ring acetal epimer mixture by addition of methanol Generated.   However, the desired intent of cyclopropane ring opening is that under the influence of cyclic oxygen, Achieved by subjecting compound 10B to oxidative ring opening with N-isosuccinimide (Hg of cyclopropane, which is conceptually similar to the conversion of 10B to 12B) (II) For reference of induced solvolysis, see Collum, D.B .; Still, W.C .; Mohamadi, F. J. Amer. Chem. Soc., 1986, 108, 2094; Collum, D.B .; Mohamadi, F .; hallock, J.S .; J. Am er. Chem. Soc., 1983, 105, 6882.). Following this precedent, this transformation is shown in FIG. It has been found that the efficiency is lower than that of cyclopropane 10B. II) Induced solvolysis was performed. Intermediate obtained as methyl glycoside 12B When tri-n-butyltin hydride is allowed to act on trimethyl To produce pyran 13B. Protection of this alcohol (see 13B → 14B) ), Subsequent cleavage of the glycosidic bond results in functional group version of virtual aldehyde 3B. An acryldithiane derivative was formed that could act as a catalyst. Epothilone and homologs A possible method for mixing the fragments related to 2B and 3B to reach Schrock (Schrock, R.R. et al., J. Amer. Chem. Soc., 1990, 112, 3875) and Grubbs ( Schwab, P. et al., Angew.Chem.Int.Ed.Engl., 1995, 34, 2039; Grubbs, R.H .; Hiller, S.J.Fu, G.C.Acc.Chem.Res., 1995,28,446; Schmalz, H.-G., Angew.Chem.Int.Ed.Eng l., 1995, 34, 1833) and Hoveyda's disclosure (Houri, A.F., et al., J. Am. Chem. S. oc., 1995, 117, 2943), complex lactams are molybdenum-mediated in substitution reactions. Built at the key intramolecular olefin macrocyclization step with intermolecular olefins (Schrock, supra; Schwab, supra) Possibilities for realizing the approach are being considered (other examples of ring-closing substitutions include: Martin, S.F.; Chen, H.-J.; Coutney, A.K.; Lia, Y.; Patzel, M.; Ramser, M N.; Wagman, A.S.Tetrahedron, 1996,52,7251; Furstner, A.; Langemann, K.J.Org.Chem., 1996,61 , 3942).   The problem was first solved with two model omega unsaturated acids 16B and 17B, Alcohols 2B to form esters 18B and 19B, respectively. (See FIG. 9). In these compounds, the actual The olefin-substituted macrocyclization was carried out according to the method described above. Compound in the case of Substitute 18B Group 20B was obtained as a mixture of E- and Z-stereoisomers [ca. 1: 1]. 20B Was carried out to obtain the homolog 2B. Olefin substitution reactions also Extended to compound 19B with a zwittermethyl group in the configuration corresponding to C4 of Ron A . Olefin substitution occurs, in which case, strangely, olefin 21B is converted to a single fruit. The product was produced in a yield of 70% (stereochemical examination showed the Z-form). Almost the same Were obtained by using Schrock's molybdenum alkylidene displacement catalyst.   Therefore, as described above, olefin substitution is a critical requirement for target systems. Attempts to construct 16-membered rings containing both oxy and thiazolyl functional groups can be made. Wear. Secosis with complete functionality required to reach epothilone No olefinic substitution reaction feasible from systems has been successful to date. Ma These negatives can be considered when determining the appropriate functional constraint pattern that is appropriate for cyclocyclization. Failure will rarely be reflected as a failure. Total Synthesis of Epothilone B: Extension of Suzuki Coupling Method   The present invention provides for the first time a total synthesis of epothilone A (1). D.Meng et al., J.Or g. Chem, 1996, 61, 7998 P. Bertinato, et al., J. Org. Chem, 1996, 61, 8000. A.Balog, et al., Angew. Chem. Int. Ed. Engl., 1996, 35, 2801. D.Meng, et al., J.Amer.Chem.S oc., 1997, 119, 10073. (For the total synthesis of epothilone A, see Z. Yang, et al., A. Engl., 1997, 36, 166) This synthesis is based on 2,2-dimethyl A highly stereoselective epoxidized Z-desoxy compound with xylan ( 23), under carefully determined conditions to produce the desired β-epoxide. To achieve. A similar myrobacterium of the genus Sorangium producing 23 is epothilone. B (2) is also generated. The latter includes antifungal screens and cytotoxic / nuclear decay It is more potent than 23 in any of the assays. G. Hofle, et al., Angew.C hem.Int.Ed.Engl. 1996, 35, 1567; D.M.Bollag, et al., Cancer Res. 1995, 55, 2325.   The first target structure was desoxyepothilone B (2) or a suitable derivative thereof. Was. By utilizing such a compound, the epoxidation of the C12-C13 double bond is accompanied. Studies of regioselectivity and stereoselectivity will be possible. The key point is that Synthesis of 2C Z-tri-substituted olefin precursors with large error range in regioselectivity It was a problem. Synthetic route to di-substitution systems (A.Balog, et al., Agnew.Chem.In t.Ed.Engl., 1996, 35, 2801), the compound 11 using 9-BBN (FIG. 4 (B)). (FIG. 1 (A)) Z-vinyl using borane 7C derived by hydroboration Palladium-mediated B-alkyl Suzuki coupling of luoide 19 (FIG. 4 (A)) (N. Miyaura, et al., J. Am. Chem. Soc. 1989, 111, 314. (For confirmation, N. Mi Yaura, A. Suzuki, Chem. Rev. 1995, 95, 2457) was used.   A preliminary approach is to apply the same concept as in 2C and apply Z-tri-substituted olefins. (Figure 17). Two important points must be presented. Primarily, It is necessary to devise a method for preparing tri-substituted homologues of vinyl iodide 8C, 19 That would be. If this goal is achievable, the question is: Z-tri-substituted olefins The required B-alkyl Suzuki coupling reaction Yes Ability. At the intermolecular level, vinyl iodide is converted to β-iodoenoate (or "B-alkyl" ("B-alkenyl" system) when not in iodoenone) form The realization of such a transformation (as opposed to a system) has not been found to be advantageous. ( The work presented here differs from some similar analogues in that there are significant differences in detail. N. Miyaura, et al., Bull.Chem. Soc. Jpn. 1982, 55, 2221; M. Ohba, et al., Te trahedron Lett., 1995, 36, 6101; C.R. Johnson, M.P. Braun, J. Am. Chem. Soc. 1993, 11 5,11014.)   FIG. 16 shows the synthesis of compound 8C. The route involves catalytic asymmetric allylation of 9C ( G.E.Keck, et al., J. Am. Chem. Soc., 1993, 115, 8467) Starting from 10C followed by acetylation. 10C Regioselective dihydroxy Ring opening of the glycol following silation produced the labile aldehyde 11C. Surprisingly, the latter reacts with phosphorane 12C (J. Chen, et al., Tetrahedro n Lett., 1994, 35, 2827), produced a small amount of Z-iodide 8C as a whole. . Borane 7C was generated from 11 as described. Compound 7C and iodide 8C Performing the coupling of FIG. 16 prepares pure Z-olefin 13C. I was able to.   Once compound 13C was obtained, a similar process to that used in connection with the synthesis of 23 was performed. Protocol was available. (Balog, et al., Angew. Chem. Int. Ed. Engl., 1996, 35,2801) Therefore, cleavage of the acetal bond gives aldehyde 14C, This has been subjected to macroaldolization (FIG. 17). The highest yield is Obtained by performing the reaction under conditions that seem to equilibrate the C3 hydroxyl group. The 3R isomer is converted via reduction of its derived C3-ketone (see compound 15C). Converted to the required 3S epimer. As described for epothilone A A kinetic controlled aldol condensation leading to a unique natural 3S conformation was achieved. I However, for all yields that reached the 3S epimer, it was better to use this protocol. Are better. Following cleavage of the C-5 triphenylsilyl ether, a continuous C3 Monoprotection of hydroxyl (t-butyldimethylsilyl), oxidation at C5 (compound 16C) and finally C3 and C7 alcohols by cleavage of the silyl protecting group. (See compound 2C).   Z-desoxyepothilone B (2C) is very fast under the conditions of presentation, substantially Has undergone regioselective and stereoselective epoxidation (exact comparisons not However, epoxidation of 2C appears to be more rapid and regioselective than in 23. Epothilone B (2) (¹1 H NMR, mass spectrum, IR, [α]_D(A. Balog, et al., Angew. Chem. Int-Ed-En) gl., 1996, 35, 2801). Thus, the present invention has for the first time opened the total synthesis of epothilone B. Show. Important features of this method include the enzymatic activity of trisubstituted vinyl vinyl iodide 8C. -Selective synthesis, palladium-mediated stereospecific coupling of formulas 7C and 8C Formation of compound 13 from the compound (a virtually unprecedented reaction in this form) and Z-decomposition. Soxyepothilone B (2C) is regioselective and stereoselective under appropriate conditions. Includes following poxification. Desmethyl epothilone A   The total synthesis of epothilones A and B has been disclosed. Balog, A., etc., Angew.Ch em., Int. Ed. Engl. 1996, 35, 2801; Nicolaou, K.C., et al., Angew. Chem., Int. Ed. . Engl. 1997, 36, 166; Nicolaou, K.C., et al., Angew. Chem., Int. Ed. Engl. 1997 , 36, 525; Schinzer, D., et al., Angew. Chem., Int. Ed. Engl. 1997, 36, 523; Su, D.-S., et al., Angew. Chem., Int. Ed. Engl. 1997, 36, 757. Epothilone antitumor The effect is very similar to taxol (Taxol ™). Hofle, G., et al. An gew. Chem., Int. Rd. Engl. 1996, 35, 1567. Taxol (paclitaxel) Although it is a clinically approved drug, its formulation is still difficult. In addition, Taki Saul contains the multidrug resistance (MDR) phenotype. Therefore, similar to taxol New drugs that have a mechanism of action and are expected to have better therapeutic potential have been seriously studied. ing. Bollag, D.M., et al., Cancer Res. 1995, 55, 2325.   The present invention is more effective than epothilones A and B, Provides Ron analogs. Natural product synthesis is sufficient for preliminary biological evaluation But do not produce enough for all developments. Structural change is a compound of synthesis A particular region that provides a considerable relief of clutter is C8 from the polypropylene domain. Elimination of the methyl group (see target system 3D). It is necessary to handle this C8 chiral center The need complicates all of the previously disclosed synthesis of epothilones. C8me Deletion of the tyl group is an early step in the synthetic approach for the diene-aldehyde cyclocondensation route. Demand big changes. Danishefsky, S.J. Chemtracts 1989, 2, 273; Meng, D., et al., J. Org. Chem. 1996, 61, 7998; Bertinato, P., et al., J. Org. Chem. 1996,61 , 8000.   As shown in FIG. 20, asymmetric crotylation of 4D (87% ee) (Brown, H.C .; Bha t, K.S> J.Am.Chem.Soc. 1986, 108, 5919), followed by TBS ether Guide 5D. The double bond is easily cleaved to give aldehyde 6D. aldehyde Couples with a dianion derived from t-butyl isobutyryl acetate To give 7D. C_5S(7D): C_5R(7D) Compound ratio (not shown) is about 1 0: 1. Weiler-type β-ketoester dianion chemistry (Weiler, L.J. Am. Chem. Soc. 1970, 92, 6702; Weiler, L .; Huckin, S.N. J. Am. Chem. Soc. 1974,96 , 1082) can be performed within the isobutyryl group, providing an alternative for a more convenient synthesis. Suggest a way. 7D C according to previous literature_ThreeDirect reduction of ketones (Evans, D.A. J. Org. Chem. 1991, 56, 741), followed by C_ThreeHydroxyl selective silyl Can be obtained in 50% yield with C_3RDesired C for isomer (not shown)_3S(Compound 8D) at a ratio of 10: 1. In reduction with sodium borohydride, C_ThreeThis gives an approximately 1: 1 mixture of epimers. Carbinow formed by debenzylation Is oxidized to an aldehyde and then methylated through a simple wittig reaction. To give olefin 9D. Treatment of this compound with TBSOTf To give Stell 10D, which is used for Suzuki coupling with vinyl iodide 12D. Used directly.   Hydroboration of 10D with 9-BBN produces intermediate 11D, Coupling with vinyl iodide 12D and in-situ TBS ester Upon cleavage, 13D (FIG. 21) is guided. After deacetylation, the hydroxy acid 14 D is available. Macrolactonization of this compound (Boden, E.P .; Keck, G. E. J. Org. Chem. 1985, 50, 2394) produces 15D, which is Later, C₈To give -desmethyldesoxyepothilone (16D). Finally, this transformation The epoxidation of the compound with dimethyldioxirane produces the desired structure 3D To . The stereoselectivity of the epoxidation is that the epoxidation of desoxyepothilone A is> 20: Surprisingly low (1.5: 1) because of the stereoselectivity of 1. C8 methyl group Deletion changes the conformational contribution of 16D, resulting in dimethyldioxirane It has been shown to reduce the β-selectivity of oxylation. To dimethyldioxirane C for the stereoselectivity of epoxidation by₈Dramatic effects of methyl and biological activity It is unclear whether the decline is related.   Compounds 3D and 16D were treated with cell culture medium and tubulin in the absence of GTP. The assembly was tested for cytotoxicity. Microtubule protein (MTP) From the bovine brain by two cycles of temperature dependent assembly and disassembly. And purified. Weisenberg, R.C. Science 1972, 177, 1104. Control Asen In the yellowtail experiment, MTP (1 mg / mL) was added to 0.1 M MES (2- (N-morpholino) ethanesulfonic acid), 1 mM GTA, 0.5mM MgCl_TwoPH6.6 assembly containing 1 mM GTP and 3M glycerol Diluted with rebuffer. Assembly is performed at 350 nm for 40 minutes at 350 nm. It was monitored optically and the change in turbidity was measured as the amount of polymer. Gaskin, F.; Cantor , C.R .; Shelanksi, M.L. J. Mol. Biol. 1974, 89, 737. The drug is 1 without GTP Tested at a concentration of 0 μM. Microtubule formation was confirmed with an electron microscope. GTP or In order to measure the stability of microtubules in the presence of the drug, after changing the reaction temperature to 4 ° C, Turbidity was measured for 40 minutes.   Cytotoxicity experiments showed an extreme decrease in activity in 8-desmethyls. Compounds 3D and 16D are approximately 200 times more active than their corresponding epothilone A (See Table 1). Former C_ThreeAnd C_FiveSAR discovery in both, here Rethinking in conjunction with the discoveries disclosed, the polypropylene sector of epothilones , Considered a particularly sensitive part of biological function. Su, D.-S., Etc., Angew.Chem.I nt. Ed. Engl. 1997, 36, 757; Meng, D., et al., J. Am. Cehm. Soc. 1997, 119. ^aThe cytotoxicity of the test compound was determined using human lymphoblastic leukemia cells CCRF-CEM or Sustains resistant to rustin and taxol (CCRF-CEM / VBL) or Etoposi As measured by the growth of a subline (CCRF-CEM / VM-1) that is resistant to the drug. XTT-microphone A broth medium tetrazolium / formazan assay was used.^b IC_5DValues were calculated from 5-6 concentrations based on median effective dose plots by computer software. Calculated using software. Biological consequences   In the table below, model system 1 is desoxyepothilone. Model system 2 is It has the following structure. Here, R ′ and R ″ are H. The model system 3 has the following structure.   As shown in Table 2, CCRF-CEM is a parent cell line. CCRF-CEM / VBL (MDR cell line) is 1143 times more resistant to taxol. CCRF -CEM / VM (Topo II mutant cell line) is 1.3 times more resistant to taxol There is only.   In terms of relative potency, synthetic epothilone is similar to natural epothilone A. For CCRF-CEM cells, the order is as follows: Taxol @ Epothilone A> Desoxyepothilone A >> Test analogs >> Models System 1. For CCRF-CEM / VBL, the order of relative capacities is as follows: Desoxyepothilone A ≧ Epothilone A >> Taxol> Test analog> Model system One. For CCRF-CEM / VM, the order of relative capacities is: Taxol @ epothilone A> desoxyepothilone A >> model system 1> similar to test object. CCRF-CEM / VM cells are collaterally sensitive to certain epothilone compounds. It is concluded that.  Referring to Table 3, the experiments were DC-3F (parent hamster lung cells), DC-3F / ADI. I (moderate multidrug resistant (MDR) cells) and DC-3F / ADX (very strong MD R cells). The relative potencies of the compounds are as follows: DC-3F: Actinomycin D> Vinblastine ≧ Epothilone A                         (0.0036μM)> Desoxyepothilone> VP-16> Ta                         Kisol (0.09 μM)> Model system 1 and test analog DC-3F / ADX: desoxyepothilone ≧ epothilone A (0.06 μM)>                         Cutinomycin D> Model system 1> Vinblastine> Trial                         Experimental analogs> Viablastin> Taxol (32.0μM) DC-3F / ADX cells (8379-fold resistant to actinomycin D)                         , VP-16, Vinblastine and Actinomy                         Although it is> 338 times (about 8379 times) resistant to Shin D,                         <20-fold more resistant to thyrone compounds. Overall, the results are similar to those of these hairless CRF-CEM cells.                                 VBL → microtubule depolymerization                                 Taxol → microtubule polymerization                                 Epo-B → microtubule polymerization Epothilone B and taxol have similar mechanisms of action (polymerization), Epothilone B synergizes with VBL, whereas Saul antagonizes VBL.                                 Taxol + VBL → antagonism                                 EpoB + taxol → antagonism                                 EpoB + VBL → synergy                           EpoB + Taxol + VBL → antagonism^* The mixing factor values <1, = 1, and> 1 are synergistic, additive, and antagonistic, respectively. Show action.   In short, epothilone and taxol are responsible for stabilizing microtubule polymerization. Have a similar mode of action. But epothilone and taxol are different It has a new character structure.   MDR cells are 1500 times more resistant to taxol (CCRF-CEM / VBL cells) , Epothilone A is only eight times more resistant and epothilone B is five times more resistant Does not indicate. For CCRE-CEM cells, EpoB is 6 times more potent than EpoA. Power, 10 times more powerful than Taxol. Desoxyepothilone B and compounds # 24 has 3-4 fold lower potency than taxol, whereas compound # 27 has Has more than twice the capacity of xol. After all, taxol and vinblastine Although antagonizing CCRF-CEM tumor cells, the combination of EpoB + vinblastine The combination shows a synergistic effect.   The relative in vitro cytotoxicity to human leukemia cells is in the following order: RU: CCRF-CEM leukemia cells EpoB (IC₅₀= 0.00035 μM; relative value = 1)> VBL (0.00063; 1 / 1.8)> # 27 ( 0.0010; 1 / 2.9)> Taxol (0.0021; 1/6)> EpoA (0.0027; 1 / 7.7)> # 2 4 (0.0078; 1 / 22.3)> # 10 (0.0095; 1 / 27.1)> # 25 (0.021; 1/60)> # 1 (0.022; 1 / 62.8)> # 20 (0.030; 1 / 85.7)> # 6 (0.052; 1/149)> # 26 (0 .055; 1/157)> # 17 (0.090; 1/257)> VP-16 (0.29; 1 / 8.29)> # 15 (0.4 4; 1/1257)> # 19 (0.96; 1/2943). CCRF-CEM / VBL MDR leukemia cells EpoB (IC₅₀= 0.0021; 1/6^*[1]^*)> # 27 (0.0072; 1 / 20.6)> # 1 (0.012; 1 / 34.3)> # 10 (0.017; 1 / 48.6)> EpoA (0.020; 1 / 57.1 [1 / 9.5])> # 6 (0.035)> # 20 (0.049)> # 24 (0.053)> # 25 (0.077)> # 22 (0. 146)> # 26 (0.197)> # 17 (0.254)> # 11 (0.262)> VBL (0.332; 1 / 948.6 [1 / 158.1])> Taxol (4.14; 1/111828 [1 / 1971.4])> VP-16 (10. 33; 1/29514 [1/4919]).^* The abilities in parentheses are for Epo B in CCRF-CEH cells.^** The abilities in square brackets are for Epo B in CCRF-CEM / VBL MDR cells. As shown in Table 9, nude mice with MX-1 xenografts were Pothilone B (35 mg / kg, mortality 0/10), Taxol (5 mg / kg, mortality 2/10; 10 mg / kg, mortality 2/6) and adriamycin (2 mg / kg, mortality 1/10; 3 mg / kg, mortality 4) / 6), it is extremely good to treat i.p. 5 times every other day starting from the 8th. Good therapeutic effect, 35mg / kg desoxyepothilone B, 5mg / kg taxo For 2 mg / kg adriamycin, tumor volume reduction was 98%, 5%, respectively. 3% and 28%. 3 out of 10 animals in the desoxyepothilone treatment group The mouse became undetectable on day 18 (see FIG. 48). ).   Prolonged with desoxyepothilone B (40 mg / kg; i.p.) starting on day 18 In the treatment, when 5 or more doses were given every other day, 5 out of 10 mice were treated on Day 28 (or Resulted in tumor loss on day 31). See Table 10. In contrast, 5 doses With extended treatment of taxol at as much as 5 mg / kg, tumors remained moderate Continued to grow at a rate, 2 out of 10 mice died of toxicity.   Daily administration of desoxyepothilone B for 6 days for 6 mice. p. Administration (25 mg / kg, as shown in previous experiments, a therapeutically effective amount) The experiment did not result in a reduction in mean body weight. (Table 13; FIG. 47). On the other hand , Epothilone B (0.6 mg / kg) i.p. for 4 days on 8 mice Caused a 33% reduction in body weight and all eight mice were toxic between days 5 and 7. Died because of.   As is evident from Table 15, desoxyepothilone B was used in MDR tumor xenografts. Taxol, bin for human (human mammalian adenocarcinoma MCF-7 / Adr xenograft) Works significantly better than blastine, adriamycin and camptothecin . This drug resistant tumor grows very aggressively, taxol and adriamycin Resistant to semi-lethal doses of. Taxol 6mg / kg i.p. Q2D x 5 reduces tumor size to 1 Adriamycin only reduced 22% on day 17 You. On the other hand, desoxyepothilone B at 35 mg / kg increased tumor size by 66 on day 17. % Reduction but no weight loss or apparent toxicity. Taxol (12mg / kg) Or LD of adriamycin (3mg / kg)₅₀Desoxye Pothilone B is more effective. In comparison, camptothecin was 1.5 and 3.0 At mg / kg, tumor size was reduced by 28% and 57%, respectively. After all, currently used Four important anti-neoplastic agents: Taxol, Adriamycin, Vinbras Desoxyepothilone B, compared to chin and camptothecin, is MDR xenotransferred. Excellent chemotherapeutic effect on the explants.

[Procedure of Amendment] Article 184-8, Paragraph 1 of the Patent Act [Submission date] October 5, 1998 (1998.10.5) [Correction contents]                                The scope of the claims         1. The following structure: (Where R, R₀And R 'are each independently H, optionally hydroxy, alkoxy, C, carboxy, carboxaldehyde linear or branched alkyl or cyclic Linear or branched alkyl which may be substituted with an acetal, fluorine, N R₁R_Two, N-hydroxyimino, or N-alkoxyimino;₁And R_Two Is independently H, phenyl, benzyl, linear or branched alkyl. R ″ is CHY ＝ CHX or H, linear or branched alkyl, Nyl, 2-methyl-1,3-thiazolinyl, 2-furanyl, 3-furanyl, 4-furanyl 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-1, X is H, straight-chain; 3-oxazolinyl, 3-indolyl or 6-indolyl; Linear or branched alkyl, phenyl, 2-methyl-1,3-thiazolinyl, 2- Furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl , Imidazolyl, 2-methyl-1,3-oxazolinyl, 3-indolyl or 6 Y is H or linear or branched alkyl; Z Are O, N (OR_Three) Or N-NR_FourR_FiveAnd R_Three, R_FourAnd R_FiveIs independent Is H or linear or branched alkyl; n is 0, 1, 2 or 3 A compound having the formula:         2. The following structure:(Where R is H, methyl, ethyl, n-propyl, n-butyl, n-hexyl , Or (CH_Two)_Three2. The compound of claim 1 having the formula -OH.         3. The following structure: (Where R, R₀And R 'are each independently H, optionally hydroxy, alkoxy, C, carboxy, carboxaldehyde linear or branched alkyl or cyclic Linear or branched alkyl which may be substituted with an acetal, fluorine, N R₁R_Two, N-hydroxyimino, or N-alkoxyimino;₁And R_Two Is independently H, phenyl, benzyl, linear or branched alkyl R "is CHY = CHX or H, linear or branched alkyl, Phenyl, 2-methyl-1,3-thiazolinyl, 2-furanyl, 3-furanyl, 4-furanyl Nil 2,2-pyridyl, 3-pyridyl, 4-pyridyl, imidasolyl, 2-methyl-1,3- Oxazolinyl, 3-indolyl or 6-indolyl; X is H, linear Or branched alkyl, phenyl, 2-methyl-1,3-thiazolinyl, 2-fura Nyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, Imidazolyl, 2-methyl-1,3-oxazolinyl, 3-indolyl or 6-a Y is H or linear or branched alkyl; Z is O, N (OR_Three) Or N-NR_FourR_FiveAnd R_Three, R_FourAnd R_FiveIs, independently, H or linear or branched alkyl; n is 0, 1, 2 or 3 Provided that R ″ is 2-methyl-1,3-thiazolinyl, 2-furanyl;₀as well as When R 'is both methyl, Z is O and n is 3, then R is H, methyl or Or not ethyl).         4. The following structure: (Where R is n-propyl, n-butyl or n-hexyl) A compound according to claim 3.         5. The following structure: (Where R, R₀And R 'are each independently H, optionally hydroxy, alkoxy, C, carboxy, carboxaldehyde linear or branched alkyl or cyclic Linear or branched alkyl which may be substituted with an acetal, fluorine, N R₁R_Two, N-hydroxyimino, or N-alkoxyimino;₁And R_Two Is independently H, phenyl, benzyl, linear or branched alkyl. R ″ is CHY ＝ CHX or H, linear or branched alkyl, Nyl, 2-methyl-1,3-thiazolinyl, 2-furanyl, 3-furanyl, 4-furanyl 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-1, X is H, straight-chain; 3-oxasolinyl, 3-indolyl or 6-indolyl; Linear or branched alkyl, phenyl, 2-methyl-1,3-thiazolinyl, 2 -Furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl , Imidazolyl, 2-methyl-1,3-oxazolinyl, 3-indolyl or 6 Y is H or linear or branched alkyl; Z Are O, N (OR_Three) Or N-NR_FourR_FiveAnd R_Three, R_FourAnd R_FiveIs independent Is H or linear or branched alkyl; n is 0, 1, 2 or 3 A compound having the formula:         6. The following structure: (Where R is H, methyl, ethyl, n-propyl, n-butyl, n-hexyl Ma Or hydroxypropyl).         7. The following structure:(Where R, R₀And R 'are each independently H, optionally hydroxy, alkoxy, C, carboxy, carboxaldehyde linear or branched alkyl or cyclic Linear or branched alkyl which may be substituted with an acetal, fluorine, N R₁R_Two, N-hydroxyimino, or N-alkoxyimino;₁as well as R_TwoIs independently H, phenyl, benzyl, linear or branched alkyl R "is CHY = CHX or H, straight or branched chain alkyl, Phenyl, 2-methyl-1,3-thiazolinyl, 2-furanyl, 3-furanyl, 4- Furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl -1,3-oxazolinyl, 3-indolyl or 6-indolyl; X is H , Linear or branched alkyl, phenyl, 2-methyl-1,3-thiazolinyl 2,2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl Lysyl, imidazolyl, 2-methyl-1,3-oxazolinyl, 3-indolyl or Is 6-indolyl; Y is H or linear or branched alkyl Z is O, N (OR_Three) Or N-NR_FourR_FiveAnd R_Three, R_FourAnd R_FiveIs an individual Independently, H or linear or branched alkyl; n is 0, 1, 2, or 3).         8. The following structure:A compound having the formula:         9. The following structure: (Wherein R ′ and R ″ are each independently hydrogen, linear or branched alkyl, Substituted or unsubstituted aryl or benzyl, trialkylsilyl, diarylalkyl Ylsilyl, alkyldiarylsilyl, linear or branched acyl, substituted or Unsubstituted aroyl or benzoyl; X is oxygen, (OR^*)_Two, (SR^*)_Two,-( O- (CH_Two)_n-O)-,-(O- (CH_Two)_n-S)-or-(S- (CH_Two)_n-S)- R^*Is a linear or branched alkyl, substituted or unsubstituted aryl or benzyl And R_TwoB is linear, branched or cyclic alkyl or substituted or unsubstituted An aryl or benzylboranyl moiety; n is 2, 3 or 4) Compounds.         10. The following structure: (Wherein R ′ and R ″ are each independently hydrogen, linear or branched alkyl, Substituted or unsubstituted aryl or benzyl, trialkylsilyl, diarylalkyl Ylsilyl, alkyldiarylsilyl, linear or branched acyl, substituted or Unsubstituted aroyl or benzoyl; X is oxygen, (OR^*)_Two, (SR^*)_Two,-( O- (CH_Two)_n-O)-,-(O- (CH_Two)_n-S)-or-(S- (CH_Two)_n-S)-; R^*Is a linear or branched alkyl, substituted or unsubstituted aryl or benzyl Yes; R_TwoB is a linear, branched or cyclic alkyl or a substituted or unsubstituted alkyl. A reel or benzylboranyl moiety; Y is OH, straight or branched Alkoxy, trimethylsiloxy, t-butyldimethylsiloxy or methyldiph Enylsiloxy; n is 2, 3 or 4).         11. The following structure: (Wherein R ′ and R ″ are each independently hydrogen, linear or branched alkyl, Substituted or unsubstituted aryl or benzyl, trialkylsilyl, diarylalkyl Ylsilyl, alkyldiarylsilyl, linear or branched acyl, substituted or X is oxygen, (OR) unsubstituted aroyl or benzoyl;_Two, (SR)_Two,-(O -(CH_Two)_n-O)-,-(O- (CH_Two)_n-S)-or-(S- (CH_Two)_n-S)-; n is , 2, 3 or 4).         12. R 'is TBS, R "is TPS, and X is (OMe)_TwoIn 12. The compound according to claim 11, wherein         13. The following structure:(Where R is hydrogen, linear or branched alkyl, alkoxyalkyl, Substituted or unsubstituted aryloxyalkyl, linear or branched acyl, substituted or unsubstituted X is halogen; R "is H, straight-chain; Linear or branched alkyl, phenyl, 2-methyl-1,3-thiazolinyl, 2- Furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl , Imidazolyl, 2-methyl-1,3-oxazolinyl, 3-indolyl or 6 Y is H or linear or branched alkyl; R ′ Is H, linear or branched alkyl, hydroxymethyl, hydroxypro Pill, alkyl carboxaldehyde, alkyl carboxaldehyde straight chain Or X is a branched acetal; X is a halide).         14． 14. The method according to claim 13, wherein R is acetyl and X is iodide. Compound.         15. The following structure: (Wherein R ′ and R ″ are each independently hydrogen, linear or branched alkyl, Substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkylali Ylsilyl, alkyldiarylsilyl, linear or branched acyl, substituted or X is oxygen, (OR) unsubstituted aroyl or benzoyl;_Two, (SR)_Two,-(O -(CH_Two)_n-O)-,-(O- (CH_Two)_n-S)-or-(S- (CH_Two)_n-S)-; n is 2, 3 or 4).         16. The following structure: (Where R is hydrogen, linear or branched alkyl, alkoxyalkyl, Substituted or unsubstituted aryloxyalkyl, linear or branched acyl, substituted Or unsubstituted aroyl or benzoyl; X is halogen: R 'is , H, linear or branched alkyl, alkyl carboxaldehyde, alkyl R "is H, straight-chain or cyclic acetal; Or branched alkyl, phenyl, 2-methyl-1,3-thiazolinyl, 2-fura Nyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, Imidazolyl, 2-methyl-1,3-oxazolinyl, 3-indolyl or 6-a And Y is H or linear or branched alkyl) Compound.         17． The following structure: (Where R is hydrogen, methyl, ethyl, n-propyl, n-hexyl, CO_TwoEt ,, CH_TwoOH or (CH_Two)_ThreeR ′ and R ″ are each independently hydrogen , Linear or branched alkyl, substituted or unsubstituted aryl or benzyl, tri Alkylsilyl, diarylarylsilyl, alkyldiarylsilyl, straight chain Z is branched or branched acyl, substituted or unsubstituted aroyl or benzoyl; , Hydrogen, or linear or branched alkyl).         18. The following structure: (Where R is hydrogen, linear or branched alkyl, alkoxyalkyl, Substituted or unsubstituted arylalkyl, linear or branched acyl, substituted or unsubstituted arylalkyl R 'is hydrogen, methyl, ethyl, n-propyl , N-hexyl, CO_TwoEt, , CH_TwoOH or (CH_Two)_Three-OH; X is halogen) In a method for producing a haloalkene ester, the method comprises:   (A) The following structure:Oxidatively cleaving the compound having the appropriate formula to form an aldehyde intermediate, And   (B) condensing the aldehyde intermediate with a halomethylene transfer agent under appropriate conditions To produce a Z-haloalkene ester.         19. 19. The method according to claim 18, wherein X is iodine.         20. When the halomethylene transfer agent is Ph_ThreeP = CR'I or (Ph_ThreeP⁺C HR'I) I^-19. The method of claim 18, wherein         21. The following structure: (Where R is hydrogen, linear or branched alkyl, alkoxyalkyl, Substituted or unsubstituted aryloxyalkyl, linear or branched acyl, substituted or unsubstituted Preparation of optically pure compounds having a substituted aroyl or benzoyl) In the method, the method comprises:   (A) an allyl organometallic reagent having the following structure: With an unsaturated aldehyde having the following formula: Optionally, in parallel therewith, optically decomposes the alcohol to give the following structure: Producing an optically pure alcohol having   (B) converting the optically pure alcohol produced in the step (a) into an appropriate condition Alkylating or acylating with to form an optically pure compound How to be.         22. The allyl organometallic reagent is an allyl (trialkyl) stannate A method according to claim 21.         23. Wherein the condensation step comprises a titanium tetraalkoxide and an optional active catalyst 22. The method according to claim 21, which is performed using a reagent comprising:         24. 24. The method of claim 23, wherein the optional active catalyst is S (-) BINOL. Law.         25. The following formula: (Wherein R ′ and R ″ are each independently hydrogen, linear or branched alkyl, Substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkylali Ylsilyl, alkyldiarylsilyl, linear or branched acyl, substituted or Unsubstituted aroyl or benzoyl). Then, the method is   (A) The following structure: (Where R is linear or branched alkyl, alkoxyalkyl, substituted or Unsubstituted aryloxyalkyl, trialkylsilyl, aryldialkyl Yl, diarylalkylsilyl, triarylsilyl, straight-chain or branched X is halogen, which is sil, substituted or unsubstituted aroyl or benzoyl; ) Having the following structure: (Where (OR "")_TwoIs oxygen, (OR₀)_Two, (SR₀)_Two,-(O- (CH_Two)_n-O)- ,-(O- (CH_Two)_n-S)-or-(S- (CH_Two)_n-S)-; R₀Is a linear or Is a branched alkyl, substituted or unsubstituted aryl or benzyl; n is 2, 3 or 4) and a cross-cup under appropriate conditions Ring the following structure: (Where Y is CH (OR^*)_TwoAnd R * is a linear or branched alkyl , Alkoxyalkyl, substituted or unsubstituted aryloxyalkyl) To form a cross-coupling compound   (B) subjecting the cross-coupled compound produced in step (a) to suitable conditions A method comprising deprotecting to form a ring-opened compound.         26. The following structure: In the method for producing epothilone having the method,   (A) The following structure: (Wherein R ′ and R ″ are each independently a linear or branched alkyl, substituted or Is unsubstituted aryl or benzyl, trialkylsilyl, dialkylaryl Ryl, alkyldiarylsilyl, linear or branched acyl, substituted or unsubstituted Cyclized compounds having aroyl or benzoyl) under appropriate conditions To form a deprotected cyclized compound, and oxidize the deprotected cyclized compound under appropriate conditions. And the following structure: To produce desoxyepothilone having   (B) Desoxyepothilone produced in the above step (a) is purified under appropriate conditions. A method comprising poxifying to form epothilone.         27. The following structure: (Where R₁Is hydrogen, or methyl; X is O, or each at a carbon atom A single bond halogen and OR "; R₀, R 'and R "are each independently water Alkyl, linear or branched alkyl, substituted or unsubstituted aryl or benzyl, Lialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, direct Linear or branched acyl, substituted or unsubstituted aroyl or benzoyl) In the method for producing an epothilone precursor having, the method,   (A) The following structure:Wherein R is acetyl, having the following structure: (Where Y is oxygen) with an aldehyde having the appropriate conditions To produce an aldol intermediate, which is optionally Protected under the following conditions: May produce an acyclic epothilone precursor having   (B) The acyclic epothilone precursor is subjected to an intramolecular olefin substitution under conditions that lead to intramolecular olefin substitution. Treating to form an epothilone precursor.         28. The conditions that lead to the intramolecular olefin substitution are based on the 28. The method of claim 27 in need.         29. The method according to claim 27, wherein the catalyst is a Ru or Mo complex.         30. A compound according to any one of claims 1, 3, 5, 7, and 8, and a pharmaceutical. A pharmaceutical composition for the treatment of cancer, comprising a carrier suitable for:         31. A method of treating cancer in a patient with cancer, the method comprising: 9. The method of claim 1, wherein the patient is administered a therapeutically effective amount of a compound according to any of claims 1, 3, 5, 7, and 8. Administering a substance and a pharmaceutically suitable carrier.         32. 32. The method of claim 31, wherein the cancer is a solid cancer.         33. 32. The method according to claim 31, wherein the cancer is a breast cancer.         34. The following structure: (Where R is hydrogen, linear or branched alkyl, alkoxyalkyl, Substituted or unsubstituted aryloxyalkyl, linear or branched acyl, substituted or unsubstituted Is unsubstituted aroyl or benzoyl). In a method for manufacturing a tell, the method comprises:   (A) The following structure Having the following structure: (Where R 'and R "are each independently a straight-chain or branched alkyl, Or an unsubstituted aroyl or benzoyl); Under the following conditions:To produce a compound having   (B) converting the compound produced in step (a) under the appropriate conditions into the following structure: To produce a Z-iodoalkene having   (C) Deprotecting the Z-iodoalkene produced in the step (b) under appropriate conditions Protecting and acylating to form a Z-iodoalkene ester Law.         35. The following structure: (Where R is linear or branched alkyl, alkoxyalkyl, substituted or Unsubstituted aryloxyalkyl, trialkylsilyl, aryldialkyl Yl, diarylalkylsilyl, triarylsilyl, straight-chain or branched R 'and R "are each independently silyl, substituted or unsubstituted aroyl or benzoyl; First, hydrogen, linear or branched alkyl, substituted or unsubstituted aryl or Benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiaryl Silyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl Wherein the method comprises the steps of:   (A) The following structure: (Where X is a halogen) having the following structure: (Where R^* _TwoB is a linear or cyclic alkyl, or a substituted or unsubstituted A reel or benzylboranyl moiety; Y is (OR₀)_Two, (SR₀)_Two,-(O- (CH_Two)_n-O)-,-(O- (CH_Two)_n-S)-or-(S- (CH_Two)_n-S)-; R₀ Is linear or branched alkyl, substituted or unsubstituted aryl or benzyl N is 2, 3 or 4) under appropriate conditions. Let the following structure:To produce a cross-coupled compound having   (B) subjecting the cross-coupled compound produced in step (a) to suitable conditions A method comprising deprotecting to form a ring-opened aldehyde.         36. R is acetyl; R 'is TBS; R "is T PS and R^* _TwoB is derived from 9-BBN and Y is (OMe)_TwoClaim that is Item 36. The method according to Item 35.         37. The following structure: (Wherein R ′ and R ″ are each independently hydrogen, linear or branched alkyl, Substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkyl Reelsilyl, alkyldiarylsilyl, linear or branched acyl, substituted or Is unsubstituted aroyl or benzoyl) In the method, the method comprises:   (A) The following structure:Is monoprotected under suitable conditions to give the following structure: To produce a cyclic alcohol having the formula:   (B) oxidizing the cyclic alcohol produced in the step (a) under appropriate conditions Forming a protected epothilone.         38. 38. The method of claim 37, wherein R 'and R "are TBS.         39. The following structure: In the method for producing epothilone having the method,   (A) The following structure: (Wherein R ′ and R ″ are each independently hydrogen, linear or branched alkyl, Substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkyl Reelsilyl, alkyldiarylsilyl, linear or branched acyl, substituted or Is an unsubstituted aroyl or benzoyl). Deprotected under the right conditions, the following structure: To produce desoxyepothilone having   (B) Desoxyepothilone produced in the above step (a) is purified under appropriate conditions. A method comprising poxifying to form epothilone.         40. 40. The method of claim 39, wherein R 'and R "are TBS.         41. The following structure:(Where R ′ is hydrogen, chain or branched alkyl, substituted or unsubstituted aryl) Or benzyl, trialkylsilyl, dialkylarylsilyl, alkyl Diarylsilyl, linear or branched acyl, substituted or unsubstituted aroyl or Is a cyclic diol having the formula:   (A) The following structure: (Where R is linear or branched alkyl, alkoxyalkyl, substituted or Unsubstituted aryloxyalkyl, trialkylsilyl, aryldialkyl Yl, diarylalkylsilyl, triarylsilyl, straight-chain or branched R 'is hydrogen, linear or unsubstituted aroyl or benzoyl; Or branched alkyl, substituted or unsubstituted aryl or benzyl, trialkyl Silyl, dialkylarylsilyl, alkyldiarylsilyl, linear or A branched acyl, substituted or unsubstituted aroyl or benzoyl) The aldehyde is cyclized under appropriate conditions to provide the following structure:And the enantiomer of a protected cyclic alcohol containing α- and β-alcohol components Form a mixture of enantiomers,   (B) optionally, subjecting the α-alcohol produced in step (a) to suitable conditions To produce a ketone, which is then reduced under appropriate conditions The enantiomer of a protected cyclic alcohol consisting essentially of β-alcohol To form a mer mixture, and then   (C) protecting the protected cyclic alcohol produced in steps (a) and (b) One comprising treating with a deprotecting agent under appropriate conditions to form a cyclic diol. Law.         42. 42. The method of claim 41, wherein R 'is TBS and R "is TPS. Method.         43. The following structure: (Where R is propyl, hexyl, hydroxymethyl or hydroxypro X is O; R0, R 'and R "are each independently hydrogen or Acetyl).         44. The following structure: (Where R₁Is hydrogen, methyl, ethyl, propyl, hexyl, hydroxy R is tyl or hydroxypropyl; X is O;₀, R 'and R " , Each independently being hydrogen or acetyl).         45. Any of claims 1, 2, 3, 4, 5, 6, 7, 8, 43 and 44. An effective amount of a compound according to any of the above, for inhibiting the growth of multidrug-resistant cells, and a pharmaceutically acceptable And a carrier.         46. 46. The composition of claim 45, further comprising a predetermined amount of a cytotoxic drug.         47. 47. The composition of claim 46, wherein the cytotoxic drug is an anti-cancer drug.         48. 48. The composition according to claim 47, wherein the anticancer agent is adriamycin.         49. 48. The composition according to claim 47, wherein the anticancer agent is vinblastine.         50. 48. The composition according to claim 47, wherein the anticancer agent is paclitaxel.         51. An effective amount of the compound is from about 0.01 mg / kg to about 46. The composition according to claim 45, which is 25 mg.         52. Any of claims 1, 2, 3, 4, 5, 6, 7, 8, 43 and 44. An effective amount of a compound according to any of the above, for inhibiting the growth of multidrug-resistant cells, and a pharmaceutically acceptable Contacting the mixture with the carrier to be treated with multidrug resistant cells. A method for inhibiting the growth of drug-resistant cells.         53. 53. The method of claim 52, further comprising administering a predetermined amount of a cytotoxic drug. the method of.         54. 54. The method according to claim 53, wherein the cytotoxic drug is an anticancer drug.         55. 55. The method according to claim 54, wherein the anticancer agent is adriamycin.         56. 56. The method according to claim 55, wherein the anticancer agent is vinblastine.         57. 56. The composition according to claim 55, wherein the anticancer agent is paclitaxel.         58. An effective amount of the compound is from about 0.01 mg / kg to about 56. The method according to claim 55, wherein the dosage is 25 mg.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 35/00 A61K 35/00 C07C 33/02 C07C 33/02 43/12 43/12 47/277 47 / 277 69/716 69/716 Z 69/738 69/738 Z 323/14 323/14 C07D 277/06 C07D 277/06 413/06 413/06 417/06 417/06 417/14 417/14 493/04 111 493/04 111 C07F 5/02 C07F 5/02 A // C07D 263/32 C07D 263/32 C07F 7/18 C07F 7/18 A (31) Priority claim number 60 / 047,566 (32) Priority date May 22, 1997 (May 22, 1997) (33) Priority claim country United States (US) (31) Priority claim number 60 / 047,941 (32) Priority date May 29, 1997 ( 1997.5.29) (33) Priority claim country United States (US) (31) Priority claim number 60/055 33 (32) Priority date August 13, 1997 (August 13, 1997) (33) Priority country United States (US) (81) Designated country EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, HU, ID, IL, IS, JP , KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, O, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZW (72) Inventor Baylog, Aaron United States of America New York 10028 New York East 81st Street 504 Apartment 4M (72) Inventor Bernate, Peter United States Connecticut 06371 Old Lime Long Acre Lane 1 (72) Inventor S. Daisy United States of America New York 10021 New York East Sevenif First Street 303 Apartment 1G (72) Inventor Chou, Tin-Chau United States of America New Jersey 07652 Paramus Daisy Way 5 (72) Inventor Men, Don, Fun United States of America New York 10021 New York Click East Sixty 6th Street 312 apartment instrument A (72) inventor Kamenekka, Ted United States New York 10021 New York East Sixty 6th Street 310 apartment instrument 4B (72) inventor Sorenzen, Eric, Jay United States California 72130 San Diego Kings field coat 13296

Claims (1)

[Claims]         1. The following structure: (Where R, R₀And R 'are each independently H, optionally hydroxy, alkoxy, C, carboxy, carboxaldehyde linear or branched alkyl or cyclic Linear or branched alkyl which may be substituted with an acetal, fluorine, N R₁R_Two, N-hydroxyimino, or N-alkoxyimino;₁And R_Two Is independently H, phenyl, benzyl, linear or branched alkyl. R ″ is CHY ＝ CHX or H, linear or branched alkyl, Nyl, 2-methyl-1,3-thiazolinyl, 2-furanyl, 3-furanyl, 4-furanyl 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-1, X is H, straight-chain; 3-oxazolinyl, 3-indolyl or 6-indolyl; Linear or branched alkyl, phenyl, 2-methyl-1,3-thiazolinyl, 2- Furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl , Imidazolyl, 2-methyl-1,3-oxazolinyl, 3-indolyl or 6 Y is H or linear or branched alkyl; Z Are O, N (OR_Three) Or N-NR_FourR_FiveAnd R_Three, R_FourAnd R_FiveIs independent Is H or linear or branched alkyl; n is 0, 1, 2 or 3 A compound having the formula:         2. The following structure:(Where R is H, methyl, ethyl, n-propyl, n-butyl, n-hexyl , Or (CH_Two)_Three2. The compound of claim 1 having the formula -OH.         3. The following structure: (Where R, R₀And R 'are each independently H, optionally hydroxy, alkoxy, C, carboxy, carboxaldehyde linear or branched alkyl or cyclic Linear or branched alkyl which may be substituted with an acetal, fluorine, N R₁R_Two, N-hydroxyimino, or N-alkoxyimino;₁And R_Two Is independently H, phenyl, benzyl, linear or branched alkyl. R ″ is CHY ＝ CHX or H, linear or branched alkyl, Nyl, 2-methyl-1,3-thiazolinyl, 2-furanyl, 3-furanyl, 4-furanyl Le 2,2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-1,3- Oxazolinyl, 3-indolyl or 6-indolyl; X is H, linear Or branched alkyl, phenyl, 2-methyl-1,3-thiazolinyl, 2-fura Nyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, Imidazolyl, 2-methyl-1,3-oxazolinyl, 3-indolyl or 6-a Y is H or linear or branched alkyl; Z is O, N (OR_Three) Or N-NR_FourR_FiveAnd R_Three, R_FourAnd R_FiveIs, independently, H or linear or branched alkyl; n is 0, 1, 2 or 3 ).         4. The following structure: (Where R is H, methyl, ethyl, n-propyl, n-butyl or n-hexyl) 4. The compound according to claim 3, which is syl.         5. The following structure: (Where R, R₀And R 'are each independently H, optionally hydroxy, alkoxy, C, carboxy, carboxaldehyde linear or branched alkyl or cyclic Linear or branched alkyl which may be substituted with an acetal, fluorine, N R₁R_Two, N-hydroxyimino, or N-alkoxyimino;₁And R_Two Is independently H, phenyl, benzyl, linear or branched alkyl. R ″ is CHY ＝ CHX or H, linear or branched alkyl, Nyl, 2-methyl-1,3-thiazolinyl, 2-furanyl, 3-furanyl, 4-furanyl 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-1, X is H, straight-chain; 3-oxazolinyl, 3-indolyl or 6-indolyl; Linear or branched alkyl, phenyl, 2-methyl-1,3-thiazolinyl, 2- Furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl , Imidazolyl, 2-methyl-1,3-oxazolinyl, 3-indolyl or 6 Y is H or linear or branched alkyl; Z Are O, N (OR_Three) Or N-NR_FourR_FiveAnd R_Three, R_FourAnd R_FiveIs independent Is H or linear or branched alkyl; n is 0, 1, 2 or 3 A compound having the formula:         6. The following structure: (Where R is H, methyl, ethyl, n-propyl, n-butyl, n-hexyl Or hydroxypropyl).         7. The following structure:(Where R, R₀And R 'are each independently H, optionally hydroxy, alkoxy, C, carboxy, carboxaldehyde linear or branched alkyl or cyclic Linear or branched alkyl which may be substituted with an acetal, fluorine, N R₁R_Two, N-hydroxyimino, or N-alkoxyimino;₁And R_Two Is independently H, phenyl, benzyl, linear or branched alkyl. R ″ is CHY ＝ CHX or H, linear or branched alkyl, Nyl, 2-methyl-1,3-thiazolinyl, 2-furanyl, 3-furanyl, 4-furanyl 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-1, X is H, straight-chain; 3-oxazolinyl, 3-indolyl or 6-indolyl; Linear or branched alkyl, phenyl, 2-methyl-1,3-thiazolinyl, 2- Furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl , Imidazolyl, 2-methyl-1,3-oxazolinyl, 3-indolyl or 6 Y is H or linear or branched alkyl; Z Are O, N (OR_Three) Or N-NR_FourR_FiveAnd R_Three, R_FourAnd R_FiveIs independent Is H or linear or branched alkyl; n is 0, 1, 2 or 3 A compound having the formula:         8. The following structure:A compound having the formula:         9. The following structure: (Wherein R ′ and R ″ are each independently hydrogen, linear or branched alkyl, Substituted or unsubstituted aryl or benzyl, trialkylsilyl, diarylalkyl Ylsilyl, alkyldiarylsilyl, linear or branched acyl, substituted or Unsubstituted aroyl or benzoyl; X is oxygen, (OR^*)_Two, (SR^*)_Two,-( O- (CH_Two)_n-O)-,-(O- (CH_Two)_n-S)-or-(S- (CH_Two)_n-S)-; R^* Is linear or branched alkyl, substituted or unsubstituted aryl or benzyl R;_TwoB represents a linear, branched or cyclic alkyl or a substituted or unsubstituted aryl. Or benzylboranyl moiety; n is 2, 3 or 4) Compound.         10. The following structure: (Wherein R ′ and R ″ are each independently hydrogen, linear or branched alkyl, Substituted or unsubstituted aryl or benzyl, trialkylsilyl, diarylalkyl Ylsilyl, alkyldiarylsilyl, linear or branched acyl, substituted or Unsubstituted aroyl or benzoyl; X is oxygen, (OR^*)_Two, (SR^*)_Two,-( O- (CH_Two)_n-O)-,-(O- (CH_Two)_n-S)-or-(S- (CH_Two)_n-S)-; R^* Is linear or branched alkyl, substituted or unsubstituted aryl or benzyl R;_TwoB represents a linear, branched or cyclic alkyl or a substituted or unsubstituted aryl. Or a benzylboranyl moiety; Y is OH, linear or branched Lucoxy, trimethylsiloxy, t-butyldimethylsiloxy or methyldiffe A compound having the formula: nylsiloxy; n is 2, 3 or 4.         11. The following structure: (Wherein R ′ and R ″ are each independently hydrogen, linear or branched alkyl, Substituted or unsubstituted aryl or benzyl, trialkylsilyl, diarylalkyl Ylsilyl, alkyldiarylsilyl, linear or branched acyl, substituted or X is oxygen, (OR) unsubstituted aroyl or benzoyl;_Two, (SR)_Two,-(O -(CH_Two)_n-O)-,-(O- (CH_Two)_n-S)-or-(S- (CH_Two)_n-S)-; n Is 2, 3 or 4).         12. R 'is TBS, R "is TPS, and X is (OMe)_TwoIn 12. The compound according to claim 11, wherein         13. The following structure:(Where R is hydrogen, linear or branched alkyl, alkoxyalkyl, Substituted or unsubstituted aryloxyalkyl, linear or branched acyl, substituted or unsubstituted X is halogen; R "is H, straight-chain; Linear or branched alkyl, phenyl, 2-methyl-1,3-thiazolinyl, 2- Furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl , Imidazolyl, 2-methyl-1,3-oxazolinyl, 3-indolyl or 6 Y is H or linear or branched alkyl; R ′ Is H, linear or branched alkyl, hydroxymethyl, hydroxypro Pill, alkyl carboxaldehyde, alkyl carboxaldehyde straight chain Or X is a branched acetal; X is a halide).         14． 14. The method according to claim 13, wherein R is acetyl and X is iodide. Compound.         15. The following structure: (Wherein R ′ and R ″ are each independently hydrogen, linear or branched alkyl, Substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkylali Ylsilyl, alkyldiarylsilyl, linear or branched acyl, substituted or X is oxygen, (OR) unsubstituted aroyl or benzoyl;_Two, (SR)_Two,-(O -(CH_Two)_n-O)-,-(O- (CH_Two)_n-S)-or-(S- (CH_Two)_n-S)-; n is , 2, 3 or 4).         16. The following structure: (Where R is hydrogen, linear or branched alkyl, alkoxyalkyl, Substituted or unsubstituted aryloxyalkyl, linear or branched acyl, substituted Or unsubstituted aroyl or benzoyl; X is halogen; , H, linear or branched alkyl, alkyl carboxaldehyde, alkyl R "is H, straight-chain or cyclic acetal; Or branched alkyl, phenyl, 2-methyl-1,3-thiazolinyl, 2-fura Nyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, Imidasolyl, 2-methyl-1,3-oxazolinyl, 3-indolyl or 6-a Y is H or straight-chain or branched alkyl) Compound.         17． The following structure: (Where R is hydrogen, methyl, ethyl, n-propyl, n-hexyl, CO_TwoEt ,CH_TwoOH or (CH_Two)_ThreeR ′ and R ″ are each independently hydrogen, Linear or branched alkyl, substituted or unsubstituted aryl or benzyl, tria Rukysilyl, diarylarylsilyl, alkyldiarylsilyl, linear Or branched acyl, substituted or unsubstituted aroyl or benzoyl; Z is Hydrogen or linear or branched alkyl).         18. The following structure: (Where R is hydrogen, linear or branched alkyl, alkoxyalkyl, Substituted or unsubstituted arylalkyl, linear or branched acyl, substituted or unsubstituted arylalkyl R 'is hydrogen, methyl, ethyl, n-propyl , N-hexyl, CO_TwoEt, , CH_TwoOH or (CH_Two)_Three-OH; X is halogen). In a method for producing a haloalkene ester, the method comprises:   (A) The following structure: Oxidatively cleaving the compound having the appropriate formula to form an aldehyde intermediate, And   (B) condensing the aldehyde intermediate with a halomethylene transfer agent under appropriate conditions To produce a Z-haloalkene ester.         19. 19. The method according to claim 18, wherein X is iodine.         20. When the halomethylene transfer agent is Ph_ThreeP = CR'I or (Ph_ThreeP⁺CH R'I) I^-19. The method of claim 18, wherein         21. The following structure: (Where R is hydrogen, linear or branched alkyl, alkoxyalkyl, Substituted or unsubstituted aryloxyalkyl, linear or branched acyl, substituted or unsubstituted Preparation of optically pure compounds having a substituted aroyl or benzoyl) In the method, the method comprises:   (A) an allyl organometallic reagent having the following structure: With an unsaturated aldehyde having the following formula: Optionally, in parallel therewith, optically decomposes the alcohol to give the following structure:Producing an optically pure alcohol having   (B) converting the optically pure alcohol produced in the step (a) into an appropriate condition Alkylating or acylating with to form an optically pure compound How to be.         22. The allyl organometallic reagent is an allyl (trialkyl) stannate A method according to claim 21.         23. Wherein the condensation step comprises a titanium tetraalkoxide and an optional active catalyst 22. The method according to claim 21, which is performed using a reagent comprising:         24. 24. The method of claim 23, wherein the optional active catalyst is S (-) BINOL. Law.         25. The following formula: (Wherein R ′ and R ″ are each independently hydrogen, linear or branched alkyl, Substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkylali Ylsilyl, alkyldiarylsilyl, linear or branched acyl, substituted or Unsubstituted aroyl or benzoyl). Then, the method is   (A) The following structure:(Where R is linear or branched alkyl, alkoxyalkyl, substituted or Unsubstituted aryloxyalkyl, trialkylsilyl, aryldialkyl Yl, diarylalkylsilyl, triarylsilyl, straight-chain or branched X is halogen, which is sil, substituted or unsubstituted aroyl or benzoyl; ) Having the following structure: (Where (OR "")_TwoIs oxygen, (OR₀)_Two, (SR₀)_Two,-(O- (CH_Two)_n-O)-, -(O- (CH_Two)_n-S)-or-(S- (CH_Two)_n-S)-; R₀Is linear or Branched alkyl, substituted or unsubstituted aryl or benzyl; n is 2 Under suitable conditions with a terminal olefin having With the following structure: (Where Y is CH (OR^*)_TwoR * is a linear or branched alkyl, Alkoxyalkyl, substituted or unsubstituted aryloxyalkyl) To form a cross-coupling compound,   (B) subjecting the cross-coupled compound produced in step (a) to suitable conditions A method comprising deprotecting to form a ring-opened compound.         26. The following structure: In the method for producing epothilone having the method,   (A) The following structure: (Wherein R ′ and R ″ are each independently a linear or branched alkyl, substituted or Is unsubstituted aryl or benzyl, trialkylsilyl, dialkylaryl Ryl, alkyldiarylsilyl, linear or branched acyl, substituted or unsubstituted Cyclized compounds having aroyl or benzoyl) under appropriate conditions To form a deprotected cyclized compound, and oxidize the deprotected cyclized compound under appropriate conditions. And the following structure:To produce desoxyepothilone having   (B) Desoxyepothilone produced in the above step (a) is purified under appropriate conditions. A method comprising poxifying to form epothilone.         27. The following structure: (Where R₁Is hydrogen, or methyl; X is O, or each at a carbon atom A single bond halogen and OR "; R₀, R 'and R "are each independently water Alkyl, linear or branched alkyl, substituted or unsubstituted aryl or benzyl, Lialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, direct Linear or branched acyl, substituted or unsubstituted aroyl or benzoyl) In the method for producing an epothilone precursor having, the method,   (A) The following structure:Wherein R is acetyl, having the following structure: (Where Y is oxygen) with an aldehyde having the appropriate conditions To produce an aldol intermediate, which is optionally Protected under the following conditions: May produce an acyclic epothilone precursor having   (B) under the conditions leading to intramolecular olefin substitution on said acyclic epothilone precursor Treating to form an epothilone precursor.         28. The conditions that lead to the intramolecular olefin substitution are based on the 28. The method of claim 27 in need.         29. The method according to claim 27, wherein the catalyst is a Ru or Mo complex.         30. A compound according to any one of claims 1, 3, 5, 7, and 8, and a pharmaceutical A pharmaceutical composition for the treatment of cancer, comprising a carrier suitable for:         31. A method of treating cancer in a patient with cancer, the method comprising: 9. The method of claim 1, 3, 5, 7, or 8 wherein the patient is a therapeutically effective amount. Administering a substance and a pharmaceutically suitable carrier.         32. 32. The method of claim 31, wherein the cancer is a solid cancer.         33. 32. The method according to claim 31, wherein the cancer is a breast cancer.         34. The following structure: (Where R is hydrogen, linear or branched alkyl, alkoxyalkyl, Substituted or unsubstituted aryloxyalkyl, linear or branched acyl, substituted or unsubstituted Is unsubstituted aroyl or benzoyl). In a method for manufacturing a tell, the method comprises:   (A) The following structure Having the following structure: (Where R 'and R "are each independently a straight-chain or branched alkyl, Or an unsubstituted aroyl or benzoyl); Under the following conditions:To produce a compound having   (B) converting the compound produced in step (a) under the appropriate conditions into the following structure: To produce a Z-iodoalkene having   (C) Deprotecting the Z-iodoalkene produced in the step (b) under appropriate conditions Protecting and acylating to form a Z-iodoalkene ester Law.         35. The following structure: (Where R is linear or branched alkyl, alkoxyalkyl, substituted or Unsubstituted aryloxyalkyl, trialkylsilyl, aryldialkyl Yl, diarylalkylsilyl, triarylsilyl, straight-chain or branched R 'and R "are each independently silyl, substituted or unsubstituted aroyl or benzoyl; First, hydrogen, linear or branched alkyl, substituted or unsubstituted aryl or Benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiaryl Silyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl Wherein the method comprises the steps of:   (A) The following structure: Wherein X is a halogen, having the following structure: (Where R^* _TwoB is a linear or cyclic alkyl, or a substituted or unsubstituted A reel or benzylboranyl moiety; Y is (OR₀)_Two, (SR₀)_Two,-(O- ( CH_Two)_n-O)-,-(O- (CH_Two)_n-S)-or-(S- (CH_Two)_n-S)-; R₀Is , Linear or branched alkyl, substituted or unsubstituted aryl or benzyl And n is 2, 3 or 4) under appropriate conditions. And the following structure:To produce a cross-coupled compound having   (B) subjecting the cross-coupled compound produced in step (a) to suitable conditions A method comprising deprotecting to form a ring-opened aldehyde.         36. R is acetyl; R 'is TBS; R "is T PS and R^* _TwoB is derived from 9-BBN and Y is (OMe)_TwoClaim that is Item 36. The method according to Item 35.         37. The following structure: (Wherein R ′ and R ″ are each independently hydrogen, linear or branched alkyl, Substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkyl Reelsilyl, alkyldiarylsilyl, linear or branched acyl, substituted or Is unsubstituted aroyl or benzoyl) In the method, the method comprises:   (A) The following structure:Is monoprotected under suitable conditions to give the following structure: To produce a cyclic alcohol having the formula:   (B) oxidizing the cyclic alcohol produced in the step (a) under appropriate conditions Forming a protected epothilone.         38. 38. The method of claim 37, wherein R 'and R "are TBS.         39. The following structure: In the method for producing epothilone having the method,   (A) The following structure: (Wherein R ′ and R ″ are each independently hydrogen, linear or branched alkyl, Substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkyl Reelsilyl, alkyldiarylsilyl, linear or branched acyl, substituted or Is an unsubstituted aroyl or benzoyl). Deprotected under the right conditions, the following structure: To produce desoxyepothilone having   (B) Desoxyepothilone produced in the above step (a) is purified under appropriate conditions. A method comprising poxifying to form epothilone.         40. 40. The method of claim 39, wherein R 'and R "are TBS.         41. The following structure:(Where R 'is hydrogen, linear or branched alkyl, substituted or unsubstituted Or benzyl, trialkylsilyl, dialkylarylsilyl, alkyl Rudiarylsilyl, linear or branched acyl, substituted or unsubstituted aroyl or Benzoyl), the method comprises the steps of:   (A) The following structure: (Where R is linear or branched alkyl, alkoxyalkyl, substituted or Unsubstituted aryloxyalkyl, trialkylsilyl, aryldialkyl Yl, diarylalkylsilyl, triarylsilyl, straight-chain or branched R 'is hydrogen, linear or unsubstituted aroyl or benzoyl; Or branched alkyl, substituted or unsubstituted aryl or benzyl, trialkyl Silyl, dialkylarylsilyl, alkyldiarylsilyl, linear or A branched acyl, substituted or unsubstituted aroyl or benzoyl) The aldehyde is cyclized under appropriate conditions to provide the following structure:And the enantiomer of a protected cyclic alcohol containing α- and β-alcohol components Form a mixture of enantiomers,   (B) optionally, subjecting the α-alcohol produced in step (a) to suitable conditions To produce a ketone, which is then reduced under appropriate conditions The enantiomer of a protected cyclic alcohol consisting essentially of β-alcohol To form a mer mixture, and then   (C) protecting the protected cyclic alcohol produced in steps (a) and (b) One comprising treating with a deprotecting agent under appropriate conditions to form a cyclic diol. Law.         42. 42. The method of claim 41, wherein R 'is TBS and R "is TPS. Method.         43. The following structure: (Where R is hydrogen, methyl, ethyl, propyl, hexyl, hydroxymethyl X is O; R 0, R ′ and R ″ are Each independently being hydrogen or acetyl).         44. The following structure: (Where R₁Is hydrogen, methyl, ethyl, propyl, hexyl, hydroxy R is tyl or hydroxypropyl; X is O;₀, R 'and R " , Each independently being hydrogen or acetyl).         45. Any of claims 1, 2, 3, 4, 5, 6, 7, 8, 43 and 44. An effective amount of a compound according to any of the above, for inhibiting the growth of multidrug-resistant cells, and a pharmaceutically acceptable And a carrier.         46. 46. The composition of claim 45, further comprising a predetermined amount of a cytotoxic drug.         47. 47. The composition of claim 46, wherein the cytotoxic drug is an anti-cancer drug.         48. 48. The composition according to claim 47, wherein the anticancer agent is adriamycin.         49. 48. The composition according to claim 47, wherein the anticancer agent is vinblastine.         50. 48. The composition according to claim 47, wherein the anticancer agent is paclitaxel.         51. An effective amount of the compound is from about 0.01 mg / kg to about 46. The composition according to claim 45, which is 25 mg.         52. Any of claims 1, 2, 3, 4, 5, 6, 7, 8, 43 and 44. An effective amount of a compound according to any of the above, for inhibiting the growth of multidrug-resistant cells, and a pharmaceutically acceptable Contacting the mixture with the carrier to be treated with multidrug resistant cells. A method for inhibiting the growth of drug-resistant cells.         53. 53. The method of claim 52, further comprising administering a predetermined amount of a cytotoxic drug. the method of.         54. 54. The method according to claim 53, wherein the cytotoxic drug is an anticancer drug.         55. 55. The method according to claim 54, wherein the anticancer agent is adriamycin.         56. 56. The method according to claim 55, wherein the anticancer agent is vinblastine.         57. 56. The composition according to claim 55, wherein the anticancer agent is paclitaxel.         58. An effective amount of the compound is from about 0.01 mg / kg to about 56. The method according to claim 55, wherein the dosage is 25 mg.